Bradykinin B1 receptor antagonists

ABSTRACT

Bradykinin B 1 -receptor antagonists of formula 
                 
 
are disclosed. The compounds are useful for treating diseases associated with inappropriate bradykinin receptor activity, such as diabetic vasculopathy, inflammation, pain, hyperalgesia, asthma, rhinitis, septic shock, atherosclerosis and multiple sclerosis. Pyrimidines, triazines, and anilines in which Q is imidazolyl or pyrrolyl are particularly preferred.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT application PCT/US00/19185filed Jul. 14, 2000, and published under PCT Article 21(2) in English asWO 01/05783 on Jan. 25, 2001. PCT/US00/19185 claimed the priority ofU.S. provisional application 60/143,990, filed Jul. 15, 1999. The entiredisclosures of both are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to pyrimidines, triazines, and anilines that arebradykinin B₁-receptor antagonists. The compounds are useful fortreating diseases associated with inappropriate or excessive bradykininreceptor activity, such as diabetic vasculopathy, inflammation, pain,hyperalgesia, asthma, rhinitis, septic shock, atherosclerosis andmultiple sclerosis.

BACKGROUND OF THE INVENTION

Bradykinin receptors of two classes are known. The B₁ receptor (B₁-BK)is not present in normal cells under normal conditions. In contrast, theB₂-BK receptor is normally present on many cell types or tissues.Although the B₁ receptor (B₁-BK) is not present under normal conditions,its synthesis is induced in blood vessel muscular layers duringinflammation.

Recent reports point to an important role of bradykinin B₁ receptors inphysiopathology. Dray and Perkins [Trends in Neurosci. 16, 99-104(1993)]have reviewed the possible implication of B₁ receptors in variousinflammatory states, in tissue reactions and in hyperalgesia. Alvarez etal. [Clin. Sci. 82, 513-519 (1992)] have provided evidence that B₁receptors are present in spontaneously hypertensive rats (SHR), andRegoli et al. [PCT application WO 98/07746] have provided evidence thatinappropriate B₁ receptor activity is associated with some forms ofdiabetes. In particular, it is known that capillary permeability isaugmented in the streptozotocin diabetic rat model, and the vascular BKreceptors of the portal veins of these animals have been shown toexhibit enhanced contractibility and capillary permeability in responseto the B₁-agonist desArg⁸BK. This effect was abolished by theB₁-antagonist Lys[Leu]desArg⁹BK while the B₂-antagonist HOE140 had noeffect. A similar increased sensitivity to desArg⁹BK was observed inuntreated SHR animals, prior to the establishment of hypertension, whichwas reversed by the same B₁-antagonist. These results indicate that theB₁-receptor is a target for a drug-preventive approach to diabetic orhypertensive vasculopathy.

Peptide antagonists of bradykinin receptors are known, although mostreported antagonists have activity towards B₂-receptors. There are todate very few small molecule B₁ antagonists. It would be useful to haveeffective antagonists of the B₁-BK receptor.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a genus of bradykinin B₁receptor antagonists sharing the general formula I:

wherein:

-   (a) all of X, Y and Z are CH; or (b) one of X, Y and Z is N and the    rest of X, Y and Z are CH; or (c) two of X, Y and Z are N and the    other of X, Y and Z is CH; or (d) all of X, Y and Z are N;-   A is A¹ or A²;-   A¹ is R⁴R⁵N—C(O)—-   A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—;-   Q is chosen from heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and-   W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰    and —NHC(O)R¹¹;-   R¹ is chosen from alkyl, cycloalkyl, alkenyl, C₁-C₃-alkylcycloalkyl,    heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl, C₁-C₃-alkylaryl,    heteroaryl, C₁-C₃-alkylheteroaryl, (C₁-C₃-alkyloxy)alkyl,    (C₁-C₃-alkyloxy)cycloalkyl, (C₁-C₃-alkylthio)alkyl,    (C₁-C₃-alkylthio)cycloalkyl and (C₁-C₃-alkylsulfonyl)alkyl;-   R² is H or C₁-C₃-alkyl, or R¹ and R² taken together form a 5- to    7-membered ring structure optionally containing O, S or NR¹²;-   R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ taken together    may form a 6-membered ring, which may be fused to a six-membered    saturated or aromatic carbocycle;-   R⁴ is chosen from H, aryl, heteroaryl, C₁-C₄-alkyl substituted with    from one to three aryl or heteroaryl residues,    wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂    and CH₃; G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—,    —CH₂O—, —CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower    alkyl)CH₂—, —CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—,    —CH₂SO—, —SOCH₂—, —CH₂SO₂—, and —SO₂CH₂—; and G′ is chosen from    —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —OCH₂CH₂—, —N(lower    alkyl)CH₂—, —SCH₂—, —SOCH₂— and —SO₂CH₂—;-   R⁵ is H or C₁-C₃-alkyl, with the proviso that both R³ and R⁵ cannot    be alkyl;-   R⁶ is aryl;-   R⁷ is aryl or C₁-C₃-alkylaryl;-   R⁸ is chosen from alkyl, aryl, heteroaryl, substituted alkyl,    C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl and C₁-C₄-alkylheteroaryl;-   R⁹ is chosen from H, alkyl, alkenyl, substituted alkyl, cycloalkyl,    aryl, alkoxy, heteroaryl, fluoroalkyl, C₁-C₄-alkylcycloalkyl,    (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,    (C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,    C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl;-   R¹⁰ is H or C₁-C₃-alkyl; or-   R⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structure    optionally containing O, S, SO, SO₂ or NR¹², said ring optionally    substituted with —OH, —CN, —COOH or —COOCH₃;-   R¹¹ is aryl;-   R¹² is chosen from H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and    aryl;-   R¹³ is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;-   m is zero or one; and-   n is zero or one, with the proviso that when A is A², m and n cannot    both be zero.

This genus may be considered to comprise subgenera of pyrimidines(IIa-IIc), triazines (III), anilines (IV) and pyridines (not shown):

In another aspect, the invention relates to a method of treating acondition resulting from inappropriate bradykinin receptor activitycomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound of formula I. Conditionsresulting from inappropriate bradykinin receptor activity includediabetic vasculopathy, post-capillary resistance or diabetic symptomsassociated with insulitis, inflammation, edema, liver disease, asthma,rhinitis, septic shock, pain, hyperalgesia, multiple sclerosis,atherosclerosis, Alzheimer's disease or closed head trauma. Ofparticular importance are chronic pain, pain associated withinflammation and dental pain. Diabetic symptoms associated withinsulitis include hyperglycemia, diuresis, proteinuria and increasednitrite and kallikrein urinary excretion. Stimulating hair growth orpreventing hair loss may also be accomplished by administering to asubject in need of such treatment a therapeutically effective amount ofa compound of formula I.

In another aspect, the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and compounds offormula I. The formulations may additionally comprise steroidal ornonsteroidal anti-inflammatory drugs (NSAIDS), cyclo-oxygenase (COX)inhibitors or selective cyclooxygenase-2 (COX-2) inhibitors.

In another aspect, the invention relates to compounds, useful asintermediates in the synthesis of bradykinin inhibitors. One genus ofsuch compounds is represented by formula

wherein E is halogen or methylthio and Hal is halogen. Another genus isrepresented by formulae

wherein X is —CN or halogen and L is —O—, —CH₂— or —N(CH₃)—.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of the invention are found in the class ofpyrimidines of formula II

These are compounds of formula I in which two of X, Y and Z are N andthe third is CH. Three classes of pyrimidines can be limned, dependingon which of X, Y and Z is CH The first of these is the4-pyrimidinamines, in which Z is CH. These have the formula IIa

In preferred embodiments, Q is chosen from imidazolyl, methylimidazolyl,pyrrolyl, methylpyrrolyl, pyrazolyl, methylpyrazolyl,hydroxymethylimidazolyl, (dimethylaminomethyl)imidazolyl, furanyl,methylfuranyl, thienyl, oxazolyl, thiazolyl, pyridinyl, quinolinyl,1-methylpyrimidin-2-onyl, phenyl, fluorophenyl, hydroxymethyl,tetrahydropyranyloxymethyl, imidazolylmethyl, pyrrolylmethyl, CH═N—OCH₃and

In particularly preferred embodiments Q is pyrrol-1-yl, imidazol-1-yl,furan-3-yl, 2-methylimidazol-1-yl or 4-methylimidazol-1-yl; A isR⁴R⁵N—C(O)—; W is Cl, NHR⁹, N(CH₃)R⁹, OR⁸, SR⁸, R⁸, morpholin-4-yl,

R¹ is chosen from alkyl, cycloalkyl, C₁-C₃-alkylaryl,C₁-C₃-alkylcycloalkyl, C₁-C₃-alkylheterocyclyl, andC₁-C₃-alkylheteroaryl; R², R³ and R⁵ are H; R⁴ is C₁-C₄-alkylaryl orC₁-C₄-alkylheteroaryl; R⁸ is C₁-C₄-alkylaryl; R⁹ is chosen fromhydrogen, alkyl, substituted alkyl, (C₁-C₄)-alkoxy,C₁-C₄-alkylcycloalkyl, C₁-C₄-alkylaryl, heterocyclyl,C₁-C₄-alkylheteroaryl, and C₁-C₄-alkylheterocyclyl; and m and n arezero. When W is NHR⁹, preferred values of R⁹ are hydrogen; methyl;ethyl; 2,2,2-trifluoroethyl; allyl; cyclopropyl; 2-cyanoethyl;propargyl; methoxy; methoxyethyl; cyclopropyl; cyclopropylmethyl;(methylthio)ethyl; 3-methoxypropyl; 3-pyridyl; 2-(3-pyridyl)ethyl;2-(2-pyridyl)ethyl; 3-pyridylmethyl; 4-pyridylmethyl;4-pyridylmethyl-N-oxide; 2-pyridazinylmethyl; sulfolan-3-yl;3-tetrahydrofuranyl; 2-tetrahydrofuranylmethyl; 3-(1-imidazolyl)propyl;1-t-butoxycarbonyl-4-piperidinyl;1-t-butoxycarbonyl-4-piperidinylmethyl; 2-(hydroxyimino)propyl;2-(methoxyimino)propyl; 2-oxo-1-propyl; and

wherein R¹⁴ is H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃, OH, SO₂CH₃,N(CH₃)₂ or COOH; R¹⁵ is chosen from H, OCH₃, F and Cl; and p is one ortwo. When W is

R¹² is preferably t-butoxycarbonyl, methoxyacetyl or phenyl.

In another preferred embodiment of formula IIa, A is

and R¹ is n-butyl; cyclohexylmethyl; cyclopentylmethyl; 2-methylpropyl;3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl; benzyl;2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl; 4-chlorobenzyl;2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl or 1,1-dimethylethyl; R² andR³ are H; Q is imidazolyl or pyrrolyl; W is NHR⁹; and R⁹ is alkyl,cycloalkyl or

wherein R¹⁴ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁵ is chosen from H, OCH₃ and Cl.

In another preferred embodiment of formula IIa, A is R⁴R⁵N—C(O)—; R¹ ischosen from isopropyl; n-butyl; cyclohexylmethyl; cyclopentylmethyl;naphthylmethyl; cyclohexylethyl; 2-methylpropyl; 3-methyl-1-butyl;cyclohexyl; 2,2-dimethylpropyl; benzyl; 2-thienylmethyl;1-t-butoxycarbonyl-4-piperidinyl; 4-methoxybenzyl; 4-chlorobenzyl;3,4-dichlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and1,1-dimethylethyl; R², R³ and R⁵ are H; R⁴ is are (including substitutedaryl), indanylmethyl, heteroarylmethyl, pyridinyl or

R¹⁶ is H, F, Cl, CN, NO₂, SO₂NH₂, CF₃, CH₃, COOCH₃, OCH₃, SO₂CH₃, SOCH₃,N(CH₃)₂ or COOH; and R¹⁷ is H, OCH₃ F or Cl. In these compounds, thecarbon to which R¹ and R² are attached is preferably of the R absoluteconfiguration, i.e. derivatives of D-amino acids, when m and n are zero.

In another preferred embodiment of formula IIa, which is also apreferred embodiment in other subgenera of the general formula I, R⁴ is

In this genus, one of J¹ and J² is preferably H and the other is H, Clor CN and G is chosen from —CH₂—, —CH₂CH₂—, —OCH₂—, —O— and —CH₂N(loweralkyl)-. Compounds having the R configuration at the carbon indicatedwith an asterisk have higher potency as bradykinin receptor antagonists.

In a second class of pyrimidines, the 2-pyrimidinamines, Y is CH. Thesehave the formula IIb:

Preferred embodiments are as for IIa. Particularly preferred embodimentsare those in which Q is imidazolyl, pyrrolyl, pyridinyl, fluorophenyl or2-thienyl. In these compounds, A is preferably R⁴R⁵N—C(O)—; W is H, Cl,NHR⁹ or OR⁸; R¹ is alkyl or C₁-C₃-alkylcycloalkyl; R², R³ and R⁵ are H;R⁴ is C₁-C₄-alkylaryl or C₁-C₄-alkylheteroaryl; R⁸ is C₁-C₄-alkylaryl;R⁹ is hydrogen, alkyl, fluoroalkyl, (C₁-C₄-alkoxy)alkyl,(C₁-C₄-alkylthio)alkyl, C₁-C₄-alkylcycloalkyl, C₁-C₄-alkylaryl,heterocyclyl, C₁-C₄-alkylheteroaryl, or C₁-C₄-alkylheterocyclyl; and mand n are zero. Among these, the most preferred compounds are those inwhich W is NHR⁹ and R⁹ is

wherein R¹⁴ is H, F, Cl, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃, SO₂CH₃,N(CH₃)₂ or COOH; and R¹⁵ is H, OCH₃ or Cl.

In the third class of pyrimidines, a different set of 4-pyrimidinamines,X is CH. These have the formula IIc:

Preferred embodiments are as for IIa. Particularly preferred embodimentsare those in which Q is imidazolyl or pyrrolyl and m and n are zero. Inthese compounds, A is preferably R⁴R⁵N—C(O)—; W is NHR⁹; R¹ iscyclohexylmethyl; 2-methylpropyl or 3-methyl-1-butyl; R², R³ and R⁵ areH; and R⁴ and R⁹ are benzyl or substituted benzyl.

Triazines form another subgenus of the invention according to formula I;in this subgenus, all of X, Y, and Z are N. The triazines of interesthave the formula III

Preferred embodiments are as for the pyrimidines. Particularly preferredembodiments are those in which Q is imidazolyl or pyrrolyl. In thesecompounds, A is preferably R⁴R⁵N—C(O)—; W is NHR⁹; R¹ iscyclohexylmethyl; 2-methylpropyl or 3-methyl-1-butyl; R², R³ and R⁵ areH; and R⁴ and R⁹ are benzyl or substituted benzyl.

Anilines form another subgenus of the invention according to formula Iin which all of X, Y, and Z are CH. Anilines of the invention have theformula IV:

Preferred embodiments are as for the pyrimidines. Particularly preferredembodiments are those in which Q is imidazolyl or pyrrolyl. In thesecompounds, A is preferably R⁴R⁵N—C(O)—; W is NHR⁹; R¹ is alkyl,cycloalkyl, C₁-C₃-alkylaryl or C₁-C₃-alkylcycloalkyl; R², R³ and R⁵ areH; R⁴ is C₁-C₄-alkylaryl; R⁹ is

R¹⁴ is H, Cl, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃, SO₂CH₃, N(CH₃)₂ orCOOH; R¹⁵ is H, OCH₃ or Cl; and m and n are zero.

All of the compounds falling within the foregoing parent genus and itssubgenera are useful as bradykinin inhibitors, but not all the compoundsare novel. In particular, certain pyrimidines in which Q is imidazolyland W is H, Cl, F or lower alkyl are disclosed as inhibitors of nitricoxide synthetase in PCT application WO 98/37079. The specific exceptionsin the claims below reflect applicants' intent to avoid claiming subjectmatter that, while functionally part of their invention, is notpatentable to them for reasons having nothing to do with the scope ofthe inventive concept.

“Alkyl” is intended to include linear, or branched hydrocarbonstructures and combinations thereof; hydrocarbons of 20 or fewer carbonsare generally preferred. “Lower alkyl” means alkyl groups of from 1 to 6carbon atoms. Examples of lower alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, and the like.

“Cycloalkyl” includes cycloalkyl groups of from 3 to 12 carbon atoms.Examples of “cycloalkyl” groups include c-propyl, c-butyl, c-pentyl,c-hexyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentylmethyl,norbornyl, adamantyl, myrtanyl and the like.

“Alkenyl” refers to a C₂ to C₂₀ hydrocarbon of a linear, branched, orcyclic (C₅-C₆) configuration, and combinations thereof, having one ortwo degrees of unsaturation. C₂-C₈ Alkenes are preferred. Examples ofalkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl,c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, 2,4-hexadienyl andthe like.

Alkynyl is C₂-C₈ alkynyl of a linear or branched configuration andcombinations thereof. Examples of alkynyl groups include ethyne,propyne, butyne, pentyne, 3-methyl-1-butyne, 3,3-dimethyl-1-butyne, andthe like.

C₁ to C₂₀ Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryland combinations thereof. Examples include phenethyl, cyclohexylmethyland naphthylethyl.

“Alkoxy” means alkoxy groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration and combinations thereof. Examples ofalkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers togroups containing one to four carbons.

Halogen includes F, Cl, Br, and I, with F and Cl as the preferredgroups. “Halophenyl” means phenyl substituted by 1-5 halogen atoms.Halophenyl includes pentachlorophenyl, pentafluorophenyl, and2,4,6-trichlorophenyl. “Fluoroalkyl” refers to an alkyl residue in whichone or more hydrogen atoms are replaced with F, for example:trifluoromethyl, difluoromethyl, and pentafluoroethyl,2,2,2-trifluoroethyl.

“Aryl” and “heteroaryl” mean a 5- or 6-membered aromatic orheteroaromatic ring containing 0-3 heteroatoms selected from O, N, andS; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring systemcontaining 0-3 heteroatoms selected from O, N, and S; or tricyclic 13-or 14-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, and S; each of which rings is optionallysubstituted with up to three substituents chosen independently fromlower alkyl, ═O, nitro, halogen, hydroxy, alkoxy, alkylsulfonyl;methylenedioxy, alkoxyethoxy, cyano, amino, alkylamino, dialkylamino,acylamino, aminosulfonyl, C₁-C₆-alkoxycarbonyl, carboxy,methylsulfonamido, perfluoroalkyl, phenyl, benzyl, trityl, and phenoxy.6- to 14-Membered aryl residues include, for example, benzene andnaphthalene, and the 5- to 10-membered heteroaryl residues include, forexample, imidazole, pyridine, indole, oxazole, thiophene, benzopyranone,benzodioxan, benzodioxole, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrimidinone, pyridazine,tetrazole, and pyrazole. From the exemplary heteroaryl residues, it willbe understood that heteroaryl does not imply the highest possible degreeof unsaturation, only that there be at least one fully aromatic ring(e.g. benzodioxan).

“Arylalkyl” and “alkylaryl” denote an aryl residue attached to theparent structure through an alkyl residue. The alkyl need not bestraight chain. Examples include benzyl, phenethyl, 2-phenylpropyl,4-chlorobenzyl, and the like. The alkyl may also be a fused cycloalkylsuch as indan (e.g. indan-2-yl), tetralin, and fluorene (e.gfluoren-9-yl) or a substituted alkyl, such as in 1-hydroxyindan-2-yl.“Heteroarylalkyl” denotes a residue comprising an alkyl attached to aheteroaryl ring such as pyridinylmethyl, pyrimidinylethyl, and the like.

“Heterocycloalkyl” means a cycloalkyl where one to three carbon atoms isreplaced with a heteroatom, such as O, NR(R═H, alkyl), N→O, S, SO, SO₂and the like. The term includes residues in which one or more rings isoptionally substituted with up to three substituents chosenindependently from lower alkyl, ═O, halogen, hydroxy, alkoxy, amino,alkylamino, dialkylamino, acylamino, aminosulfonyl,C₁-C₆-alkoxycarbonyl, carboxy, methylsulfonamido, perfluoroalkyl,phenyl, benzyl, trityl, and phenoxy. When two heteroatoms are separatedby a single carbon, the resulting heterocycloalkyls tend to be unstablein aqueous solutions and are therefore not preferred. Examples ofheterocycloalkyls include: tetrahydrofuran, tetrahydropyran, piperidine,pyridine-N-oxide, 2-methyl-1,3-dithiane, dioxane, and the like.

“Substituted” alkyl, alkenyl, cycloalkyl, aryl, heteroaryl orheterocycloalkyl means alkyl, alkenyl, cycloalkyl, aryl, heteroaryl orheterocycloalkyl, wherein hydrogen atoms are replaced by halogen,hydroxy, hydroxyimino, alkoxyimino, nitro, alkoxy, alkoxyethoxy, amino,alkylamino, dialkylamino, aminosulfonyl, perfluoroalkyl, phenyl, benzyl,trityl, phenoxy, amidino, guanidino, ureido, alkyl, alkylenedioxy (e.g.methylenedioxy) fluoroalkyl, carboxy (—COOH), carboalkoxy (i.e. acyloxyRCOO—), carboxyalkyl (i.e. alkoxycarbonyl —COOR), carboxamido (—CONH₂),acylamino (RCONH—), cyano, carbonyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl,arylsulfonamido, heteroaryl, heterocyclyl, phenoxy, benzyloxy, orheteroaryloxy.

Most of the compounds described herein contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures. Optically active (R)— and (S)—isomers are prepared as described below using chiral synthons or chiralreagents, or resolved using conventional techniques. When a specificchirality is intended, it is indicated by the conventional wedge anddash notation; a simple single bond emanating from a chiral centerimplies no particular stereochemistry. Usually such compositions will bemixtures of enantiomers. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

As stated above, pharmaceutical compositions comprise a pharmaceuticallyacceptable carrier and compounds of formula I. The formulations mayadditionally include steroidal or nonsteroidal anti-inflammatory drugs(NSAIDS), cyclo-oxygenase (COX) inhibitors or selective cyclooxygenase-2(COX-2) inhibitors. Preferred drugs for inclusion in pharmaceuticalformulations include: NSAIDs such as arylpropionic acids, arylaceticacids, arylbutyric acids, fenamic acids, arylcarboxylic acids,pyrazoles, pyrazolones, salicylic acids; and oxicams; cyclooxygenaseinhibitors such as ibuprofen and salicylic acid derivatives; selectivecyclooxygenase-2 inhibitors such as rofecoxib and celecoxib; steroidalantiinflammatory drugs such as finasteride, beclomethasone andhydrocortisone.

Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

-   Ac=acetyl-   BNB=4-bromomethyl-3-nitrobenzoic acid-   Boc=t-butyloxy carbonyl-   Bu=butyl-   c-=cyclo-   DBU=diazabicyclo[5.4.0]undec-7-ene-   DCM=dichloromethane=methylene chloride=CH₂Cl₂-   DEAD=diethyl azodicarboxylate-   DIC=diisopropylcarbodiimide-   DIEA=N,N-diisopropylethyl amine-   DMAP=4-N,N-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   DVB=1,4-divinylbenzene-   EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline-   Fmoc=9-fluorenylmethoxycarbonyl-   GC=gas chromatography-   HATU=O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOAc=acetic acid-   HOBt=hydroxybenzotriazole-   Me=methyl-   mesyl=methanesulfonyl-   MTBE=methyl t-butyl ether-   NMO=N-methylmorpholine oxide-   PEG=polyethylene glycol-   Ph=phenyl-   PhOH=phenol-   PfP=pentafluorophenol-   PPTS=pyridinium p-toluenesulfonate-   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   rt or RT=room temperature-   sat'd or sat.=saturated-   s-=secondary-   t-=tertiary-   TBDMS=t-butyldimethylsilyl-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TMOF=trimethyl orthoformate-   TMS=trimethylsilyl-   tosyl=p-toluenesulfonyl-   Trt=triphenylmethyl

The compounds of the invention are synthesized as follows.

Amino functionalized TentaGel resin 1 (10 g 5.2 mmole) was suspended in50 mL of CH₂Cl₂ and treated with 3.73 g of linker acid 62 (15.6 mmole),3.25 mL of DIC (20.8 mmole), and 63 mg of DMAP (0.52 mmole). After 48 hat room temperature, 3.77 g of linker acid 62, 3.25 mL of DIC and 2.1 gHOBt were added. The mixture was shaken at room temperature for 17 h andthen washed with DMF twice, CH₂Cl₂ ten times to give resin 63. Theresins 63 was treated with amine R⁴NH₂ 64 and Na(OAc)₃BH indichloroethane at room temperature for 36 h then washed with methanol 5times and methylene chloride 5 times to give resin-bound amine 65. Theamine was coupled with an N-Fmoc amino acid (66) by treatment with HATUand i-Pr₂NEt in methylene chloride at room temperature for 48 h toprovide resin 67. Fmoc on resin 67 was removed by treatment with 30%piperidine in DMF and the resulting resin-bound amine was then reactedwith fluoropyrimidine 68, i-Pr₂NEt in DMSO:nBuOH (1:1) at 100° C. for 18h and then washed with methanol, CH₂Cl₂ to give resin bound product 69.The final product was cleaved off resin by treatment with TFA for 3 h togive product 70.

The fluoropyrimidine 68 was prepared by stirring together 315 mg6-imidazolyl-2,4-difluoropyrimidine (1.7 mmole), 265 mg of3-chlorobenzylamine and 0.5 mL of i-Pr₂NEt in 30 mL of THF at 50° C. for16 h, then cooling to room temperature. The reaction was diluted withethyl acetate and washed with saturated NH₄Cl, H₂O, brine, dried overMgSO₄ and concentrated. The crude product was purified by flashchromatography (eluted with 4:5:1 EtOAc:hexanes:MeOH) to give 160 mg of68 (more polar product as compared the other regioisomer).

Scheme 2 depicts a similar synthesis to that of Scheme 1, except thelinker is photolytically cleavable instead of acid cleavable. As shownin Scheme 2, 2.5 g of amino functionalized TENTAGEL™ resin 1 (0.70mmole) was suspended in 10 mL of CH₂Cl₂ and treated with 0.882 g oflinker acid 2 (2.1 mmole), 0.44 mL of DIC (2.8 mmole), and 17 mg of DMAP(0.14 mmole). The mixture was shaken at room temperature for 17 h andthen washed with CH₂Cl₂ ten times to give resin 3.

1.13 g of resin 3 was treated with 50% TFA-CH₂Cl₂ at room temperaturefor 1.5 h and then washed with CH₂Cl₂ ten times, 15% Et₃N—CH₂Cl₂ for 10min, and CH₂Cl₂ for 5 times. The deprotected resin was then suspended in12 mL of CH₂Cl₂ and treated with 449 mg of N-Fmoc-D-Leu (1.27 mmole),483 mg of HATU (1.27 mmole), and 0.50 mL of i-Pr₂NEt (2.85 mmole). Themixture was shaken for 19 h at ambient temperature and then washed 5times to give resin 4. Fmoc on resin 4 was removed by treatment with 30%piperidine in DMF and the resulting resin-bound amine (0.32 mmole) wasthen reacted with 182 mg of 6-imidazolyl-2,4-difluoropyrimidine (0.64mmole), 0.34 mL of i-Pr₂NEt (1.92 mmole) in 10 mL of DMF at 23° C. for17 h and then washed with DMF, CH₂Cl₂ to give resin 5. This reactionalso produces the other regioisomer 5a,

which provides entry into the series of pyrimidines of general formulaIIa above. The two are separated after cleavage. For simplicity, onlythe further transformations in the IIb series are shown in Scheme 2. Theresin-bound fluoride 5 was treated with 0.25 mL of3,4-dichlorobenzylamine (1.6 mmole) in 15 mL of DMF and 0.30 mL ofHünig's base at 60° C. for 18 h and then cooled to room temperature andwashed with DMF, CH₂Cl₂. The final product was cleaved off resin byphotolysis in MeOH for 17 h to give 49.2 mg of crude product.Purification by flash chromatography (eluted with 5:5:1EtOAc:hexanes:MeOH) gave 27.2 mg of 6a (later determined to be mixtureof two regioisomers with 1:1 ratio).

Scheme 3 illustrates a solution phase synthesis via chloropyrimidinesand Scheme 4 illustrates a solution phase synthesis viafluoropyrimidines. As shown in Scheme 3, EDC (5.18 g, 26.47 mmole) wasadded into a solution of N-Boc-D-leucine (6.0 g, 24.07 mmole) in 250 mLof CH₂Cl₂, followed by 2.99 mL of 4-chlorobenzylamine (24.07 mmol). Themixture was stirred at room temperature for 4 h then diluted with ethylacetate and washed with 1N HCl twice, saturated NaHCO₃ and brine twice,dried over MgSO₄ and concentrated to give 7.92 g of crude amide productwhich was treated with 50% TFA in CH₂Cl₂ at room temperature for 4 h.The solvent was removed and the residue was taken up into ethyl acetateand washed with 2 N NaOH aqueous solution, then brine, dried over MgSO₄and concentrated to give amine product 7 quantitatively. Three hundredninety milligrams of the free amine 7 (1.1 mmole) was treated with 0.6mL of i-Pr2NEt and 500 mg 6-imidazolyl-2,4-dichloropyrimidine (2.0mmole) in DMF at 50° C. for 16 hr, then diluted with ethyl acetate andwashed with saturated NH₄Cl, H₂O, brine, dried over MgSO₄ andconcentrated and purification by flash chromatography (eluted with8:10:1 EtOAc:Hexanes:MeOH) to give 200 mg of 8 and 130 mg of 9 Ninetytwo milligrams of 9 (0.21 mmole) in 3 mL of n-butanol was treated with0.9 mL of 3-chlorobenzylamine and 1 mL of i-Pr₂NEt at 100° C. for 16 h,then cooled to room temperature, diluted with ethyl acetate and washedwith saturated NH₄C₁, H₂O, brine, dried over MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (eluted with 4:5:1EtOAc:Hexanes:MeOH) o give 97.2 mg of 10.

Alternatively, as illustrated in Scheme 4, 280 mg of the free amine 7(1.1 mmole) was treated with 0.25 mL of i-Pr₂NEt and 200 mg of6-imidazolyl-2,4-difluoropyrimidine (1.1 mmole) in THF at roomtemperature for 13 hr, then diluted with ethyl acetate and washed withsaturated NH₄Cl, H₂O, brine, dried over MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (eluted with 8:10:1EtOAc:hexanes:MeOH) to give 35 mg of 11 (less polar product) and 80 mgof 12 (more polar product). Four hundred fifty milligrams of 12 (1.08mmole) in 50 mL of THF or n-butanol was treated with 1.7 g of3-chlorobenzylamine and 5 mL of i-Pr₂NEt at 80° C. for 16 h then dilutedwith ethyl acetate and washed with saturated NH₄Cl, H₂O, brine, driedover MgSO₄ and concentrated. The crude product was purified by flashchromatography (eluted with 6:12:1 EtOAc:hexanes:MeOH) to give 350 mg of10.

Scheme 5 illustrates a synthesis of a member of the subgenus in which R¹is heterocycloalkyl. According to Scheme 5 a dry 500 mL round bottomflask (oven-heated/argon cooled), was charged with 25 g (109.2 mmol) ofBoc-isonipecotic acid (21). The flask was purged with argon, and 150 mLof dry THF were injected by syringe into the air-free system. Themixture was then stirred while being cooled to 0° C., and an oil-bubblerwas attached, then 131 mL of a 1M solution of borane/THF (131 mmol) wereinjected into the solution slowly, and the solution was stirred for ½hour. Methanol was dripped into the solution slowly until bubbles ceasedto be evolved. The solution was washed with 200 mL of a saturated sodiumbicarbonate solution, and extracted twice with ethyl acetate, and theorganic layer was dried over magnesium sulfate. The yield of thereaction was 22.44 g (96%) of the 22 product as a white solid. ¹H NMR inCDCl₃: a 3H multiplet from 0.85-1.2 ppm, a 9H singlet at 1.45 ppm, a 4Hmultiplet 1.455-1.8 ppm, a 2H broad signal at 2.65 ppm, a 1H broadsignal at 3.45 ppm, and a 1H broad signal at 3.6 ppm.

A 250 mL round bottom flask was charged with 5.8 g (27 mmol) of 22, 8.5g (32.37 mmol) of triphenylphosphine, and 2.2 g (32.37 mmol) ofimidazole. One hundred milliliters of methylene chloride were added, andthe resulting solution was stirred at 0° C. for about 5 minutes.Finally, 8.2 g (32.37 mmol) of iodine were added and the solution wasstirred at 0° C. for 5 minutes and at room temp for about 1 hour. Thereaction mixture was diluted with 200 mL of hexane, and thetriphenylphosphine oxide precipitate was filtered off (this was repeateduntil all precipitate was removed). The crude mixture was purified byflash chromatography using a 5%-10% ethyl acetate/hexane solvent system.A Phosphomolybdic acid stain (PMA), was used to see the product on theTLC plate. The resulting yield of pure 23 as an oil was 2.6 g (30%). ¹HNMR in CDCl₃: 2H quartet at 1.1 ppm (J=12 Hz), a 9H singlet at 1.4 ppm,a 1H broad signal at 1.55 ppm, a 2H doublet at 1.75 (J=12 Hz), a 2Hbroad signal at 2.65 ppm, a 2H doublet at 3.05 ppm (J=6 Hz), and a 2Hbroad signal at 4.1 ppm. The R_(f)=0.13 using a 5% ethyl acetate/hexanesolvent system.

A dry 250 mL round bottom flask (oven heated/argon cooled), was chargedwith 1.3 g (5.113 mmol) of N-(diphenylmethylene) glycine ethyl ester.The flask was purged with argon, and 100 mL of dry THF were injectedinto the air-free system. The resulting solution was cooled to −78° C.with stirring, and 6.2 mL (6.15 mmol) of a 0.1M solution of sodiumhexamethyldisilazane in THF were injected into the solution. Thereaction was stirred at −78° C. for ½ hr, and a solution of 2 g of 23 indry THF was injected into the system. The solution was stirred at −78°C. for 1 hr, at 0° C. for 1 hr, and at room temp overnight. The reactionmixture was washed with a solution of 1 g (6.15 mmol) of citric acid inwater, and diluted with 200 mL of ethyl acetate. The organic layer wasextracted and dried over magnesium sulfate. The crude mixture waspurified by flash chromatography using a 10% ethyl acetate/hexanesolvent system. The yield was 1.45 g (61%) of solid product 24. ¹H NMRin CDCl₃: A 3H broad multiplet from 0.8-1.15 ppm, a 4H broad signal at1.25 ppm, a 9H singlet at 1.4 ppm, a 2H broad signal at 1.5 ppm, a 1Hbroad triplet at 1.85 ppm, a 2H broad quartet at 2.6 ppm, a 2H broadsignal at 3.95 ppm, a 2H broad signal at 4.15 ppm, a 2H triplet at 7.15ppm (J=3.6 Hz), a 6H multiplet from 7.25-7.5 ppm, and a 2H doublet at7.6 ppm (J=9 Hz). The R_(f)=0.22 suing a 10% ethyl acetate/hexanesolvent system. ESI MS at 465 MH+.

A 100 mL round bottom flask was charged with 0.35 g (0.75 mmol) of 24,and 20 mL of ethanol were added to the flask. With stirring, 0.5 mL of a50% (by weight) solution of hydroxylamine was added followed by 0.5 mLof glacial acetic acid (5 minutes later). The reaction was stirred for10 minutes, until the starting material disappeared by TLC. The reactionmixture was diluted with 100 mL ethyl acetate, 20 mL of a brine solutionwas added, followed by basification using 0.5 M NaOH. The organic layerwas extracted, and the aqueous layer was then extracted with two 20 mLportions of methylene chloride. The combined organic layers were driedover magnesium sulfate. The crude mixture was purified by flashchromatography using a 55% ethyl acetate/hexane solvent system. Aninhydrin stain was used to see the product spot on the TLC plate. Theyield of pure 25 as an oil was 0.25 g (96%). ¹H NMR in CDCl₃: A 1Hmultiplet from 0.9-1.05 ppm, a 3H broad triplet at 1.1 ppm, a 3H tripletat 1.25 ppm (J=6 Hz), an 11H broad signal at 1.4 ppm, a 3H multipletfrom 1.5-1.8 ppm, a 2H broad triplet at 2.7 ppm, a 3H quartet at 3.45ppm (J=3.6 Hz), and a 4H multiplet from 4-4.2 ppm. The R_(f)=0.22 usinga 55% ethyl acetate/hexane solvent system.

A 50 mL round bottom flask was charged with 0.310 g (1 mmol) of 25 andmL of DMF. With stirring, 0.22 g (1 mmol) of the pyrimidine/imidazolesubunit, and 0.35 mL (2 mmol) of diisopropylethylamine (Hünig's base)were added. The mixture was stirred at 90° C. overnight. The reactionmixture was diluted with 200 mL of ethyl acetate, and washed with water.The organic layer was extracted and dried over magnesium sulfate. Thecrude mixture was purified by flash chromatography using an 80%-90%ethyl acetate/hexane solvent system. The yield of the reaction was 0.14g of the regio-isomer with substitution of the pyrimidine at the2-position and 0.12 g (25%) of the desired regio-isomer 36 (oil), (totalyield is 54%). ¹H NMR in CDCl₃: a 1H multiplet from 0.9-1.05 ppm, a 3Hbroad triplet at 1.15 ppm, a 2H triplet at 1.3 ppm (J=6 Hz), a 9Hsinglet at 1.45 ppm, a 2H broad signal at 1.7 ppm, a 2H broad signal at1.85 ppm, a 2H broad triplet at 2.65 ppm, a 2H broad signal at 4.1 ppm,a 2H quartet at 4.2 ppm (J=2.4 Hz), a 1H broad signal at 4.9 ppm, a 1Hdoublet at 6.05 ppm (J=9 Hz), a 1H broad singlet at 6.3 ppm, a 1Hsinglet at 7.15 ppm, a 1H singlet at 7.5 ppm, and a 1H singlet at 8.3ppm. The R_(f) of the desired regio-isomer was about 0.22 using an 80%ethyl acetate/hexane solvent system. The pure product gave a molecularion of 480, MH+.

A 50 mL round bottom flask was charged with 0.12 g (0.25 mmol) of 26,0.142 g (1 mmol) of 3-chlorobenzylamine, and 5 mL of dry n-butanol. Thesolution was stirred at 120° C. overnight. The reaction mixture wasdiluted with 200 mL of ethyl acetate, and washed with water. The organiclayer was extracted and dried over magnesium sulfate. The crude mixturewas purified by flash chromatography using a 90%-95% ethylacetate/hexane solvent system. The yield was 0.125 g (87%) of 27 as anoil. ¹H NMR in CDCl₃: a 1H triplet at 0.9 ppm (J=6), a 2H broad signalat 1.1 ppm, a 3H triplet at 1.25 ppm (J=4.8 Hz), a 9H singlet at 1.45ppm, a 5H broad signal at 1.65 ppm, a 2H broad signal at 2.6 ppm, a 4Hbroad signal at 4.1 ppm, a 2H doublet at 4.55 ppm (J=6 Hz), a 1H broadsignal at 4.7 ppm, a 1H doublet at 5.4 ppm (J=9 Hz), a 1H singlet at5.75 ppm, a 1H singlet at 7.1 ppm, a 3H singlet at 7.2 ppm, a 1H singletat 7.35 ppm, a 1H singlet at 7.5 ppm, and a 1H singlet at 8.25 ppm. TheR_(f) of the product was about 0.28 using an 80% ethyl acetate/hexanesolvent system. The pure product gave a molecular ion of 584, MH+.

A 50 mL round bottom flask was charged with 0.125 g (0.214 mmol) of 27and 10 mL of THF. With stirring, a solution of 0.09 g (2.14 mmol) oflithium hydroxide in 10 mL of water was added. The solution was heatedat 55° C. for 2 hr. The reaction mixture was diluted with 200 mL ofethyl acetate, and washed with a solution of 0.412 g (2.14 mmol) ofcitric acid in water to neutralize the excess base present. The organiclayer was extracted and dried over magnesium sulfate. The crude mixturewas purified by flash chromatography using an 95% ethyl acetate/methanolsolvent system. The yield was 0.1 g (83%) of pure 28 as a white solid.¹H NMR in CDCl₃: a 1H broad signal at 0.9 ppm, a 3H broad signal at 1.1ppm, a 2H triplet at 1.25 ppm (J=6 Hz), a 9H singlet at 1.4 ppm, a 4Hbroad signal at 1.65 ppm, a 2H broad signal at 2.45 ppm, a 3H broadsignal at 4 ppm, a 2H broad signal at 4.3-4.8 ppm, a 1H broad signal at5.85 ppm, a 1H singlet at 7.05 ppm, a 3H singlet at 7.15 ppm, a 1Hdoublet at 7.25 ppm (J=3.6), a 1H singlet at 7.5 ppm, and a 1H singletat 8.5 ppm. The R_(f) of the product was about 0.08 using a 95% ethylacetate/methanol solvent system. The pure product gave a molecular ionof 556, consistent with its molecular weight of 555, MH+.

A 50 mL round bottom flask was charged with 0.099 g (0.178 mmol) of 28and 20 mL of methylene chloride. With stirring, 0.048 g (0.356 mmol) of1-hydroxybenzotriazole (HOBT) and 0.068 g (0.356 mmol) of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), wereadded to the solution, then 1 mL of DMF was added to aid in solubility,and the solution was stirred for 20 minutes, until the acid intermediatespot disappeared by TLC. Fifty milligrams (0.356 mmol) of4-chlorobenzylamine was added to the solution and it was stirred for 2hrs. The reaction mixture was diluted with 200 mL of ethyl acetate andwashed successively with solutions of 0.5 M HCl, 0.5 M NaOH, and brine.The organic layer was extracted and dried over magnesium sulfate. Thecrude mixture was purified by flash chromatography using 100%-98% ethylacetate/methanol as the solvent system. The yield was 0.085 g (71%) ofpure 29 as an oil. ¹H NMR in CDCl₃: a 4H multiplet from 0.9-1.3 ppm, a9H singlet at 1.4 ppm, a 5H broad signal at 1.6 ppm, a 1H multiplet from1.75-2.15 ppm, a 2H broad signal at 2.6 ppm, a 2H singlet at 3.85 ppm, a1H broad signal at 4.05 ppm, a 4H multiplet from 4.3-4.6 ppm, a 1Hdoublet at 5.3 ppm (J=6), a 1H singlet at 5.7 ppm, a 2H singlet at 7.1ppm, a 7H multiplet from 7.15-7.3 ppm, a 1H singlet at 7.45 ppm, and a1H singlet at 8.25 ppm. The R_(f) of the product was about 0.24 using a95% ethyl acetate/methanol solvent system. The pure product gave amolecular ion of 679, consistent with its molecular weight of 678 amu.

A 50 mL round bottom flask was charged with 0.020 g (0.03 mmol) of 29and 3 mL of methylene chloride. With stirring, 1.5 mL (0.02 mmol) oftrifluoroacetic acid was added, and the solution was stirred for about20 minutes, until the Boc-containing intermediate disappeared by TLC.The reaction mixture was diluted with 10 mL toluene and evaporatedtwice. The product 30 was diluted with 50 mL ethyl acetate, and washedwith 0.5 M NaOH. ¹H NMR in CDCl₃: a 5H multiplet from 0.75-1 ppm, a 5Hmultiplet from 1.5-1.8 ppm, a 1H singlet at 1.95 ppm, a 2H quartet at2.6 ppm (J=14), a 1H broad signal at 3.1 ppm, a 2H singlet at 3.65 ppm,a 4H multiplet from 4.-4.7 ppm. A 1H singlet at 5.9 ppm, a 9H multipletfrom 7.05-7.15 ppm, a 1H singlet at 7.5 ppm and a 1H singlet at 8.3 ppm.The pure product gave a molecular ion of 579, consistent with itsmolecular weight of 578 amu.

As outlined in Scheme 6, a 500 mL round bottom flask was charged with 10g (55.84 mmol) of 31, 84 g (558.4 mmol) of sodium iodide, 20.63 g (55.84mmol) of t-butyl ammonium iodide, and 250 mL acetone. The mixture wasstirred at reflux overnight. The reaction mixture was filtered toeliminate excess sodium iodide, and was diluted with 100 mL hexane. Themixture was filtered again to remove more of the remaining sodiumiodide. This was repeated until no precipitate formed when the mixturewas diluted with hexane. The reaction yield was 9.66 g (77%) of pure2-(iodomethyl)tetrahydro-2H-pyran 32 as an oil. ¹H NMR in CDCl₃ wasconsistent with structure. R_(f)=0.55, using a 2% ethyl acetate/hexanesolvent system and a phosphomolybdic acid stain. The product did notgive a mass spec signal.

A dry 100 mL round bottom flask (oven heated/argon cooled) was chargedwith 3.2 g (11.80 mmol) of N-(diphenylmethylene) glycine ethyl ester andpurged with argon. Thirty-five milliliters of dry DMPU and 15 mL of dryTHF were injected by syringe into the air-free system. The resultingsolution was cooled to −78° C., and 17.70 mL (1.5 mmol) of a 0.1Msolution of sodium hexamethylsilazane in THF was injected into thesystem, which was then stirred at −78° C. for 20 minutes. Finally, anair-free solution of 4 g (17.70 mmol) of 32 in dry THF was injected intothe system, which was then stirred at −78° C. for ½ hr, 0° C. for ½ hr,and room temp overnight. The reaction mixture was diluted with 300 mL ofethyl acetate and washed 5 times with 50 mL portions of water to removethe DMPU. The organic layer was extracted and dried over magnesiumsulfate. The crude mixture was purified by flash chromatography 4-11%ethyl acetate/hexane solvent system. The yield of the reaction was 1.57g of the less polar diastereomer of 33, and 0.33 g of the more polardiastereomer of 33. The overall yield was 1.9 g (44%). ¹H NMR in CDCl₃was consistent with structures. The diastereomers have partial overlapby TLC, R_(f)=0.55 using a 5% ethyl acetate/hexane solvent system. Theproduct gave a molecular ion of 366, consistent with its molecularweight of 365.

Note: Throughout the rest of the synthesis, the procedures involve theuse of the more polar diastereomer, for the sake of clarity.

The deprotection and work-up of 33 to give 34 follows the same procedureas that for the isonipecotic analogue (see the synthesis of 25 in thatsequence).

The crude mixture was purified by flash chromatography using an 80-90%ethyl acetate/hexane solvent system and a ninhydrin stain. The yield forthe reaction was 68%. ¹H NMR in CDCl₃ was consistent with structures.The R_(f)=0.15 using a 90% ethyl acetate/hexane solvent system. Theproduct gave MH+@ 202.

The coupling and work-up of 34 with the dichloropyrimidine-pyrroleintermediate follows the same procedure as that for the isonipecoticanalogue with the dichloropyrimidine-imidazole intermediate (see thesynthesis of 26 in that sequence). The crude mixture was purified byflash chromatography using a 10-20% ethyl acetate/hexane solvent system.The yield for the reaction was 25% for the desired more polarregio-isomer, and 62% for the total yield for both regio-isomers. ¹H NMRin CDCl₃ was consistent with structure. The R_(f)=0.15 using a 10% ethylacetate/hexane solvent system. The product gave MH+@ 379.

The remaining steps from 35 to 36 follow the corresponding procedures asfor the isonipecotic analogue (see Scheme 5). The crude 36 was purifiedby flash chromatography using a 16-25% ethyl acetate/hexane solventsystem. ¹H NMR in CDCl₃ was consistent with structure. The R_(f)=0.55using a 20% ethyl acetate/hexane solvent system. The product gave MH+ at615.

Scheme 7 depicts an exemplary synthesis wherein m> zero and A=A². ToBoc-D-leucinol (2.7 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4mmol), and phthalimide (1.82 g, 12.4 mmol) in 25 mL of dry THF was addedDEAD dropwise. The solution was stirred at room temperature overnight,concentrated and taken up in MeOH. To this solution was added hydrazine(780 mL, 24.8 mmol) and heated to reflux for 2 hours. The mixture wasallowed to cool to room temperature, and the white precipitate filtered.The mother liquor was concentrated, taken up in EtOAc and washed with 1NHCl. The aqueous layer was then cooled in an ice bath, basified with 3NNaOH, and extracted with EtOAc. The organic layer was dried over K₂CO₃and concentrated to yield 41 as a clear oil. (0.75 g, 3.5 mmol, 28%).

To 41(0.3 g, 1.4 mmol) in 15 mL pyridine was added 4-chlorobenzoylchloride (194 mL, 1.5 mmol) and the mixture was stirred at roomtemperature for 4 hours. The reaction was poured into 200 mL water andthe precipitate filtered. The resulting solid was taken up in DCM andwashed with saturated NaHCO₃ and 1M KHSO₄. The organic layer was driedover MgSO₄ and concentrated to yield 42 as a pale white solid. (0.30 g,0.84 mmol, 61%).

One hundred sixty-five milligrams of 42 (0.46 mmol) was taken up in 10mL of DCM and 5 mL TFA was added. After 30 minutes the solution wasconcentrated, taken up in DMF and basified with excess triethylamine. Tothis was added 2,4-dichloro-6-imidazolylpyrimidine (100 mg, 0.46 mmol)and the mixture stirred at room temperature overnight. The reactionmixture was concentrated and the resulting oil purified on a silica gelcolumn, eluting with 2% MeOH/DCM to yield 43. (42 mg, 0.1 mmol, 21%).

To 43 (30 mg, 0.07 mmol) in 10 mL n-butanol was added DIEA (60 mL, 0.35mmol) and 3-chlorobenzylamine (200 mL, 1.4 mmol), and the reaction washeated to 100° C. overnight. The solution was concentrated and theresulting oil purified on a silica gel column, eluting with 5% MeOH/DCMto yield 44 as a foam. (31 mg 0.06 mmol, 82%).

Scheme 8 illustrates a similar synthesis to that of Scheme 7 in which Ais R⁴NH—.

Two hundred seventy milligrams of 41 (1.25 mmol), 4-chlorobenzaldehyde(193 mg, 1.4 mmol) and sodium triacetoxyborohydride (0.4 g, 1.9 mmol)were combined in 20 mL dichloroethane and stirred at room temperatureovernight. The mixture was then concentrated, taken up in DCM and washedwith saturated NaHCO₃, dried over MgSO₄ and concentrated to yield 45which was used without further purification. (0.40 g, 1.2 mmol, 94%).

To 45 (0.35 g, 1.03 mmol) in DCM cooled in an ice bath was addedtrifluoroacetic anhydride (145 μl, 1.03 mmol) slowly. After 10 minutesthe solution was concentrated, taken up in DCM and washed with 1M KHSO₄.The organic layer was dried over MgSO₄ and concentrated to yield 46which was used without further purification. (0.32 g, 0.75 mmol, 75%).

Three hundred twenty milligrams of 46 (0.73 mmol) was taken up in 10 mLof DCM and 5 mL TFA was added. After 30 minutes the solution wasconcentrated, taken up in DMF and basified with excess triethylamine. Tothis was added 2,4-dichloro-6-imidazolylpyrimidine (190 mg, 0.88 mmol)and stirred at room temperature overnight. The reaction mixture wasconcentrated and the resulting oil purified on a silica gel column,eluting with 2% MeOH/DCM to yield 47. (100 mg, 0.19 mmol, 27%).

To 47 (100 mg, 0.19) in 5 mL of n-butanol was added DIEA (60 μl, 0.35mmol) and 3-chlorobenzylamine (200 μL, 1.4 mmol) and heated to 100° C.overnight. The solution was concentrated and the resulting oil purifiedon a silica gel column, eluting with 5% MeOH/DCM to yield 48 as a foam.(10 mg 0.02 mmol, 9%).

A solution of 48 (10 mg 0.02 mmol) in 10 mL of MeOH:H₂O:THF (1:1:1) wasrefluxed for 6 hours with excess LiOH. The solution was concentrated,taken up in DCM and washed with brine. The organic layer was dried overMgSO₄ and concentrated to yield 49. (6 mg, 0.01 mmol, 50%).

According to Scheme 9, a solution of 2,4-dichloro-6-methylpyrimidine(710 mg, 4.36 mmol) in 4.5 mL of dry THF was added dropwise to asolution of freshly prepared LDA (466 mg, 4.36 mmol) in 17.5 mL of dryTHF at −78° C. After stirring for additional 15 min, the solution of theanion formed was cannulated into a solution ofcamphorsulfonyloxaziridine (1.0 g, 4.36 mmol) in 11 mL of dry THFmaintained at −78° C. The reaction mixture was stirred in dryice-acetone bath for 1 h, then quenched with acetic acid and brought toroom temperature. Aqueous work up and chromatography (silica gel,hexane:ethyl acetate, 4:1) gave 300 mg of 72.

A solution of 2,4-dichloro-6-hydroxymethylpyrimidine (1.8 g, 10.0 mmol),dihydropyran (1.26 g, 15 mmol) and PPTS (502 mg, 2.0 mmol) in 20 mL ofdry chloroform was stirred for 1 h at RT. TLC indicated complete absenceof the starting material. Aqueous work up and chromatography (silicagel, hexane:ethyl acetate, 85:15) gave 1.02 g of the THP ether 73.

A solution of leucine amide 74 (254 mg, 1.0 mmol), THP ether (263 mg, 1mmol) and Et₃N (101 mg, 1 mmol) in 10 mL of dry THF was refluxed for 24h. Evaporation of the solvent, followed by aqueous work up andchromatography (silica gel, hexane:ethyl acetate, 65:35) gave 174 mg ofthe desired isomer 75.

A solution of 75 (174 mg, 0.36 mmol) and 3-chlorobenzylamine (142 mg,1.0 mmol) in 15 mL of n-butanol was refluxed overnight. The solvent wasremoved in vacuo and the residue was purified by chromatography (silicagel, ethyl acetate) to provide 52 mg of 6.

A solution of 76 (52 mg, 0.085 mmol) and PPTS (50 mg, 0.2 mmol) in 12 mLof 5:1 ethanol:water was refluxed overnight. Evaporation of the solventand aqueous work up provided 33 mg of alcohol 77, which was used in thenext step without purification.

A solution of alcohol 77 (140 mg, 0.28 mmol) and Et₃N (85 mg, 0.84 mmol)in 3 mL of dry DMSO was treated with pyridine. SO₃ complex (134 mg, 0.84mmol) at RT. Aqueous work up gave the aldehyde 78 in almost quantitativeyield.

A solution of aldehyde 78 (25 mg, 0.05 mmol), NH₂OMe.HCl (42 mg, 0.5mmol) and anhydrous NaOAc (41 mg, 0.5 mmol) in 5 mL of ethanol wasrefluxed overnight. Aqueous work up and chromatography (silica gel,hexane:ethyl acetate, 3:1) gave 10 mg of oxime ether 80, (M+H)⁺: 529.2.

A mixture of aldehyde 78 (135 mg, 0.27 mmol), toluenesulfonylmethylisocyanide (TOSMIC) (195 mg, 1 mmol) and K₂CO₃ (138 mg, 1 mmol) in 5 mLof methanol was refluxed for 5 h. Evaporation of the solvent andchromatography (silica gel, hexane:ethyl acetate, 1:2) gave 57 mg ofoxazole 81, (M+H)⁺: 539.2.

According to Scheme 10, n-BuLi (10 mmol, 4 mL of 2.5 M solution inhexane) was added at −78° C. to a solution of1-dimethylsulfamoylimidazole (1.75 g, 10 mmol) in 50 mL of dry ether.After stirring for 1 h, the suspension of the anion formed was quicklytransferred by a syringe to a suspension of 2,4-dichloropyrimidine (1.49g, 10 mmol) in 80 mL of dry ether maintained at −30° C. After stirringat −30° C. for 30 min, the temperature was brought to 0° C. andmaintained there for additional 30 min. The reaction mixture wasquenched with a mixture of acetic acid (0.64 mL) water (0.1 mL) and THF(2 mL). Immediately afterwards, a solution of DDQ (2.27 g, 10 mmol) in10 mL of THF was added and the reaction mixture was stirred overnight.After diluting with ethyl acetate (25 mL), the reaction mixture wasfiltered through celite and the filtrate was washed with water threetimes. Finally, a quick wash with ice cold 0.5% NaOH was employed to getrid of the hydroquinone. Evaporation of the solvent and chromatography(silica gel, hexane:ethyl acetate 3:1) provided 550 mg of 83.

A solution of leucine amide 74 (200 mg, 0.79 mmol),2,4-dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine (254 mg,0.79 mmol) and Et₃N (88 mg, 0.87 mmol) in 3 mL of DMF was stirred at RTfor 5 days. Aqueous work up and chromatography (silica gel, ethylacetate) gave 200 mg of 84, (M+H)⁺: 540.1.

A solution of chloropyrimidine 84 (200 mg, 0.37 mmol) and3-chlorobenzylamine (568 mg, 4 mmol) in 10 mL of n-butanol was refluxedovernight. The solvent was removed in vacuo and the residue waschromatographed (silica gel, ethyl acetate:methanol, 98:2) to provide 12mg of 85, (M+H)⁺: 538.2.

A solution of2,4-Dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine 83 (246 mg,0.76 mmol) in 10 mL of 1.5 N HCl was refluxed for 1 h. After cooling toRT, the pH was adjusted to 8.5 with aq NaHCO₃ and the product wasextracted into CH₂Cl₂. After drying the CH₂Cl₂ layer was evaporated togive 110 mg of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine. A mixture of2,4-dichloro-6-(imidazole-2-yl)pyrimidine (121 mg, 0.56 mmol), K₂CO₃(100 mg, 0.72 mmol) and CH₃I (2.280 g, 1 mL, 16 mmol) in 15 mL of dryacetone was refluxed for 48 h. After cooling to RT, the solvent wasevaporated and the residue was partitioned between water and CH₂Cl₂. TheCH₂Cl₂ layer was washed successively with water and brine, and then thesolvent was evaporated to give 75 mg of2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86.

A solution of 2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86 (72mg, 0.31 mmol), leucine amide 74 (100 mg, 0.39 mmol) and Et₃N (100 mg, 1mmol) in 3 mL of DMF was heated to 70° C. overnight. Aqueous work up andchromatography (silica gel, hexane:ethyl acetate, 1:3) gave 67 mg of 87,(M+H)⁺: 447.2.

According to Scheme 11, a solution of 3-chlorophenethyl alcohol (5 g, 32mmol) in 50 mL of dry MeCN was treated with dibromotriphenylphosphorane(13.54 g, 32 mmol) for 24 h. The reaction mixture was filtered and thesolvent was removed in vacuo. The residue was triturated with hexane andfiltered. Evaporation of the solvent provided 6.5 g of 3-chlorophenethylbromide. A solution of the bromide (6.5 g, 29.6 mmol) in 50 mL of dryDMSO containing NaCN (2.17 g, 44 mmol) was heated to 100° C. overnight.The reaction mixture was diluted with water and extracted with ether.The ether layer was washed with water, dried and the solvent was removedin vacuo. Chromatography (silica gel, hexane:ethyl acetate, 4:1)provided 3.7 g of nitrile 89.

A 2 M solution of Me₃Al in toluene (18 mL, 36 mmol) was slowly added toa stirred suspension of NH₄Cl (2.07 g, 38.7 mmol) in 20 mL of drytoluene at 5° C. After the addition was over, the reaction mixture waswarmed to RT and stirred for 2 h. Then, a solution of nitrile 89 (3.7 g,22.4 mmol) in 15 mL of dry toluene was added and the solution was heatedto 80° C. for 18 h. After cooling to RT, the reaction mixture was pouredinto a slurry of 15 g of silica gel in 50 mL of CHCl₃ and stirred for 5min. The silica gel was filtered and washed with methanol. The filtrateand washings were combined and the solvent was removed. The residueobtained was partitioned between water and methylene chloride.Evaporation of the methylene chloride provided 2.7 g of amidine 90.

A solution of amidine 90 (2.7 g, 14.8 mmol) and diethyl malonate (2.37g, 14.8 mmol) in 50 mL of dry ethanol containing freshly prepared NaOEt(1.0 g, 14.8 mmol) was refluxed for 15 h. Afer cooling to RT, thesolvent was removed and the residue was dissolved in water. The pH wasadjusted to 4 and the precipitated solid was filtered and dried toprovide 2.6 g of 2-(3-chlorophenethyl)-4,6-dihydroxy-pyrimidine. Amixture of 2-(3-chlorophenethyl)-4,6-dihydroxypyrimidine (2.6 g, 10.38mmol), POCl₃ (25 mL) and N,N-diethylaniline (6 mL) was refluxedovernight. After cooling to RT, the reaction mixture was poured into icewater and the product was extracted into ether. The ether layer waswashed successively with water and brine and the solvent was evaporated.Chromatography (silica gel, hexane:ethyl acetate, 9:1) of the oilprovided 2.6 g of the 2-(3-chlorophenethyl)-4,6-dichloropyrimidine (91).

A solution of 2-(3-chlorophenethyl)-4,6-dichloropyrimidine (286 mg, 1mmol) 91 in 3 mL of dry DMF was treated with 1-trimethylsilylimidazole(140 mg, 1 mmol) and CsF (152 mg, 1 mmol) at RT overnight. Aqueous workup and chromatography (silica gel, hexane:ethyl acetate, 1:1) gave 200mg of 4-chloro-2-(3-chlorophenethyl)-6-(1-imidazolyl)pyrimidine (92).

A solution of 4-chloro-2-(3-chlorophenethyl)-6-(1-imidazolyl)pyrimidine92 (100 mg, 0.31 mmol), leucine amide 74 (95 mg, 0.372 mmol) and DIEA(129 mg, 1 mmol) in 2 mL of DMF was heated to 80° C. for 24 h. Aqueouswork up and chromatography (silica gel, ethyl acetate:methanol, 98:2)gave 105 mg of 93, (M+H)⁺: 537.4.

According to Scheme 12, a solution of4,6-dichloro-2-methylthiopyrimidine (1.95 g, 10 mmol) in 30 mL of dryTHF was cooled to 0° C. and treated with a solution of MeMgBr (14 mL of1.4 M solution, 19.6 mmol). After overnight stirring at RT, the reactionmixture was quenched with sat. NH₄Cl. The organic layer washed withbrine, dried and evaporated. The residue was purified by chromatography(silica gel, hexane:ethyl acetate, 9:1) to provide 1.3 g of4-chloro-6-methyl-2-methylthiopyrimidine (95).

Dry DMF (2 mL) was cooled to −5° C. and POCl₃ (15.4 mmol, 2.31 g) wasadded dropwise. The cooling bath was removed and the reaction mixturewas stirred for 15 min at RT. 4-chloro-6-methyl-2-methylthiopyrimidine(1.3 g, 7.47 mmol) was added and the contents were heated to 60° C.overnight. The reaction mixture was poured on ice, pH was adjusted to 9and the precipitated product was filtered. The precipitate was washedwith water and dried to provide 1.3 g of the enaminone 96.

A mixture of enaminone 96 (675 mg, 2.6 mmol) and N-methylurea (232 mg,3.14 mmol) in 5 mL of acetic acid was heated to 100° C. for 2 h. Aqueouswork up and chromatography (silica gel, ethyl acetate:methanol, 98:2)gave 100 mg of pyrimidinone 97.

A solution of 97 (100 mg, 0.37 mmol), leucine amide 74 (100 mg, 0.34mmol) and DIEA (60 mg, 0.46 mmol) in 3 mL of DMF was heated to 80° C.for 2 days. Aqueous work up followed by chromatography (silica gel,ethyl acetate:methanol, 95:5) gave 30 mg of 98.

A mixture of 98 (30 mg, 0.061 mmol) and NaIO₄ (263 mg, 1.23 mmol) in 6mL of 1:1 methanol:water was stirred overnight at RT. Aqueous work upgave 10 mg of the crude sulfoxide 99.

The sulfoxide 99 (10 mg, 0.002 mmol) and 3-chlorobenzylamine (27 mg, 0.2mmol) in 2 mL of n-butanol were heated to reflux for 24 h. Aqueous workup after removal of n-butanol, followed by chromatography (silica gel,CH2Cl2:methanol, 95:5) gave 2 mg of 100, (M+H)⁺: 580.2.

According to Scheme 13, a solution of (R)-leucinol (1.288 g, 11 mmol) inmL of THF at RT was added dropwise to a stirred suspension of potassiumhydride (0.485 g, 12.1 mmol) in 25 mL of dry THF. After overnightstirring at RT, a solution of 4-chlorobenzylbromide (2.25 g, 11 mmol) in5 mL of THF was added dropwise. The stirring was continued foradditional 3 h. The solvent was evaporated and the residue waspartitioned between water and ether. The ether layer was washed withbrine, dried and the solvent was removed in vacuo to provide 2.1 g ofether 101.

A solution of 4-chloro-6-(1-imidazolyl)-2-methylthiopyrimidine (227 mg,1 mmol), aminoether 101 (242 mg, 1 mmol) and Et₃N (101 mg, 1 mmol) in 4mL of DMF was heated to 70° C. for 24 h. Aqueous work up andchromatography (silica gel, hexane:ethyl acetate, 1:1) provided 300 mgof thioether 103.

A solution of the thioether 103 (300 mg, 0.7 mmol) in 10 mL of CH₂Cl₂was treated with m-CPBA (428 mg, 1.74 mmol) at 0° C. overnight. Theprecipitate was filtered and the filtrate was evaporated to obtain crudesulfone 104. No starting material or intermediate sulfoxide was detectedby MS.

A solution of sulfone 104 (100 mg, 0.22 mmol) and 3-chlorobenzylamine (2mmol) in 3 mL of n-butanol was refluxed for 24 h. Aqueous work up afterremoval of n-butanol, followed by chromatography (silica gel, ethylacetate) gave 22 mg of 105, (M+H)⁺: 525.2.

According to Scheme 14, a solution of4-chloro-6-(1-imidazolyl)-2-methylthiopyrimidine (227 mg, 1 mmol),(R)-leucinol (117 mg, 1 mmol) and Et₃N (101 mg, 1 mmol) in 3 mL of DMFwas heated to 70° C. for 24 h. Aqueous work up and chromatography(silica gel, hexane:ethyl acetate, 1:3) gave 290 mg of 106.

A solution of alcohol 106 (290 mg, 0.94 mmol) and Et₃N (303 mg, 3 mmol)in 5 mL of DMSO was treated with pyridine-sulfur trioxide complex (477mg, 3 mmol) at RT overnight. Aqueous work up gave 280 mg of the crudealdehyde 107 which was used in the next step without purification.

A mixture of aldehyde 107 (280 mg, 0.91 mmol), Na(OAc)₃BH (290 mg, 1.37mmol), 4-chlorobenzylamine (142 mg, 1 mmol) and HOAc (60 mg, 1 mmol) in10 mL of dry 1,2-dichloroethane was stirred at RT overnight. Aqueouswork up and chromatography (silica gel, CH₂Cl₂:methanol:NH₄OH, 95:5:0.5)gave 135 mg of 108.

A solution of amine 108 (130 mg, 0.3 mmol) and boc-anhydride (214 mg, 1mmol) in 5 mL of THF was stirred at RT overnight. Aqueous work up afterremoval of the solvent, provided 60 mg of the Boc-protected amine 109.

A mixture of the Boc-protected amine 109 (60 mg, 0.11 mmol) and m-CPBA(83 mg, 0.33 mmol) in 20 mL of 1:1 CH₂Cl₂:phosphate buffer was stirredat 0° C. for 2 h and then kept in the refrigerator overnight. Themethylene chloride layer was filtered and the solvent was removed toprovide the crude sulfone. A solution of the sulfone in 5 mL ofn-butanol containing 10 eq of 3-chlorobenzyl-amine was refluxed for 20h. The solvent was removed in vacuo and the residue was treated with 2:1CH₂Cl₂:TFA for two days. After removal of the solvent, the residue wastaken in water and basified. The precipitated product was extracted intoCH₂Cl₂. Evaporation of the CH₂Cl₂ layer gave 6 mg of 110, (M+H)⁺: 524.2.

According to Scheme 15, a solution of Ph₃P (262 mg, 1 mmol) andphthalimide (147 mg, 1 mmol) in 3 mL of dry THF was treated with asolution of diethyl azodicarboxylate (174 mg, 1 mmol) in 2 mL of dry THFat RT. After stirring for 5 min, a solution of alcohol 111 (257 mg, 1mmol) in 5 mL of dry THF was added and the stirring was continued for 3days. The solvent was removed and the residue was chromatographed(silica gel, hexane:ethyl acetate, 4:1) to obtain 320 mg of phthalimide112.

Three hundred twenty milligrams (0.83 mmol) of phthalimide 112 and 50 mg(1 mmol) of NH₂NH₂.H₂O in 5 mL of ethanol was refluxed for 2 h. Thesolvent was removed and the residue was partitioned between CH₂Cl₂ and1N NaOH. Evaporation of the organic layer after drying provided theprimary amine. The amine was coupled with 4-chlorobenzoic acid (130 mg,0.83 mmol) using HATU (1 eq) in DMF containing 2 eq of DIEA. The amidewas purified by chromatography (silica gel, hexane:ethyl acetate, 1:1),yield 200 mg. The boc group was removed by stirring in TFA:CH₂Cl₂ (1:2)at RT overnight to provide 113.

A solution of 4-chloro-6-(1-imidazolyl)-2-methylthiopyrimidine (227 mg,1 mmol), TFA salt of amine 113 (220 mg, 1 mmol) and Et₃N (303 mg, 3mmol) in 3 mL of DMF was heated to 80° C. overnight. Aqueous work up andchromatography (silica gel, hexane:ethyl acetate, 1:3) gave 130 mg of114.

A solution of the thioether 114 (130 mg, 0.27 mmol) in 20 mL of CH₂Cl₂was treated with m-CPBA (196 mg, 0.8 mmol) at 0° C. for 1 h, and thenleft in a refrigerator overnight. The reaction mixture was filtered andthe crude sulfone 115 was isolated by evaporation of the filtrate.

A solution of sulfone 115 (130 mg, 0.25 mmol), 3-chlorobenzylamine (72mg, 0.5 mmol) and Et₃N (50 mg, 0.5 mmol) in 4 mL of n-butanol was heatedto reflux for 20 h. Aqueous work up and chromatography (silica gel,ethyl acetate:methanol, 99:1) gave 66 mg of 116, (M+H+): 578.2.

The corresponding sulfonamide 117 was prepared by a similar procedure tothat of Scheme 15, using 4-chlorobenzenesulfonyl chloride in place of4-chlorobenzoyl chloride, (M+H)⁺: 614.2.

Compounds in which X, Y and Z are CH and Q is pyrrole are prepared asshown in Scheme 16.

According to Scheme 16, a solution of 3,5-dinitroaniline (1.83 g, 10mmol) and 2,5-dimethoxytetrahydrofuran in 20 mL of HOAc was refluxedovernight. The reaction mixture was poured into water and extracted withEtOAc. The ethyl acetate layer was washed with water followed by aqNaHCO₃ and brine. After drying, the solvent was removed to provide 1.52g of 1-(3,5-dinitrophenyl)pyrrole.

A mixture of 1-(3,5-dinitrophenyl)pyrrole (1.52 g, 6.52 mmol) andSnCl₂.2H₂O (4.4 g, 19.57 mmol) in 30 mL of ethyl acetate was stirredover weekend at RT. The solvent was removed and the residue was taken inwater. The aqueous layer was basified with 1 N NaOH to dissolve the tinsalts, and the product was extracted into ethyl acetate. Chromatography(silica gel, hexane:ethyl acetate, 4:1) of the crude product provided440 mg of 1-(3-amino-5-nitrophenyl)pyrrole.

A solution of benzyl ester 120 (222 mg, 1 mmol), DIEA (129 mg, 1 mmol)and triflic anhydride (282 mg, 1 mmol) in 5 mL of dry CH₂Cl₂ was stirredat 0° C. for 1.5 h. TLC in hexane:ethyl acetate (4:1) indicated completeconversion of the starting material. The solvent was removed and thecrude triflate 121 was used for the next step.

A solution of 1-(3-amino-5-nitrophenyl)pyrrole (203 mg, 1 mmol) andtriflate 121 in 15 mL of 1,2-dichloroethane containing collidine (121mg, 1 mmol) was refluxed for 24 h. Aqueous acidic work up, followed bychromatography (hexane:ethyl acetate, 4:1 gave 95 mg of 122.

The ester 122 (95 mg, 0.23 mmol) was treated 250 mg of NaOH in 5 mL of95:5 methanol:water. After overnight stirring at RT, the solvent wasremoved and the residue was taken in water. The pH was adjusted to 3 andthe precipitated acid was extracted into ethyl acetate. Evaporation ofthe ethyl acetate layer gave 57 mg of 123.

To a solution of carboxylic acid 123 (57 mg, 0.18 mmol) in 3 mL of dryDMF containing 2 eq of DIEA, 1 eq of HATU was added. After 5 min 1 eq of4-chlorobenzyl amine was added and the stirring was continued overnight.The crude product 124 obtained after aqueous work up was used directlyfor the next step.

Amide 124 was reduced with SnCl₂.2H₂O (5 eq) in ethyl acetate asdescribed earlier. The aniline 125 was purified by chromatography(silica gel, hexane:ethyl acetate, 1:1), yield 7 mg.

A mixture of aniline 125 (7 mg, 0.017 mmol), Na(Oac)₃BH (6 eq) and3-chlorobenzaldehyde (6 eq) in 2 mL of 1,2-dichloroethane was stirred atRT overnight. Aqueous work up and chromatography (silica gel,hexane:ethyl acetate, 62:38) gave 3 mg 126, (M+H)⁺: 535.1.

To a solution of N-BOC-cyclohexyl alanine (200 mg, 0.74 mmol) in 2 mL ofdry methylenechloride was added dropwise hydrazine (0.1 mL, 0.89 mmol)and EDC (159 mg, 0.81 mmol) at 23° C. The reaction mixture was stirredfor 48 h, then washed with NH₄Cl, water, and brine to give 150 mg of132.

A solution of hydrazide 132 (72.4 mg, 0.254 mmol) and imidate 133 (52mg, 0.28 mmol) in 2 mL of dry acetonitrile was stirred for 16 h at RT.TLC indicated complete absence of the starting material. Solvent wasremoved and the crude product was treated with TFA:methylenechloride,1:1, and washed with 1 N NaOH, water and brine to give 16.2 mg of thetriazole 134.

A solution of triazole 134 (16.2 mg, 0.06 mmol), fluoropyrimidine 68(27.3 mg, 0.09 mmol) and iPr₂NEt (0.02 mL, 0.12 mmol) in 1 mL of drynBuOH was refluxed for 16 h. Evaporation of the solvent, followed byaqueous work up and chromatography (silica gel, hexane:ethylacetate:methanol, 4:4:1) gave 9.0 mg of the desired product 136.

Compounds of the invention in which A¹ is

and in which A¹

are synthesized as shown in Scheme 17. In both cases the Boc protectinggroup is cleaved with trifluoroacetic acid and the amine is reactedfurther as already described.

A solution of diazo ketone 51 (2.89 g, 9.78 mol.) in 60 mL of ether wascooled to −20° C. and 2 mL of 48% HBr (960 mg, 11.85 mol.) was addeddropwise. After 35 minutes, an additional 0.5 mL of HBr (240 mg, 2.96mol.) was added and the stirring was further continued for 25 min. TLC[hexane:ethyl acetate (4:1)] indicated complete absence of the startingmaterial and appearance of the less polar α-bromoketone. Cold aqueouswork-up and chromatography on silica gel with hexane:ethyl acetate(85:15) gave 2.7 g of the pure α-bromoketone 52. ¹H NMR (CDCl₃):5.00-4.80 (m, 1H), 4.64-4.50 (m, 1H), 1,90-0.90 (m, 22H). Theα-bromoketone is reacted with 4-chlorobenzamidine in refluxingchloroform to provide the imidazole 53 according to the method of Nagaoet al. [Heterocycles 42, 517-523 (1996)]. The α-bromoketone is reactedwith 4-chlorothiobenzamide in dioxane to provide the thiazole 54according to the method of Nan'Ya et al. [J. Heterocycl. Chem. 32,1299-1302 1995].

Scheme 19 illustrates the synthesis of an example in which m is 1. Asolution of Boc-α-cyclohexyl-D-alanine (1.085 g, 4.0 mmol) andN-methylmorpholine (404 mg, 4.0 mmol) in 15 mL of dry THF was cooled to−10° C. and a solution of isobutyl chloroformate (544 mg, 4.0 mmol) in 5mL of THF was added dropwise. After stirring for additional 10 min, anethereal solution of diazomethane (ca. 9 mmol) was added slowly. Afterovernight stirring at RT, TLC indicated formation ofdiazoketone(R_(f)≈0.4 in hexane:ethyl acetate 4:1). The excessdiazomethane was destroyed by addition of aq HOAc and the solvent wasevaporated in vacuo. The residue obtained was partitioned between etherand water. The ether layer was successively washed with aq NaHCO₃, waterand brine. After drying (MgSO₄), the ether was evaporated to give thediazoketone 140 as a pale yellow oil.

The diazoketone was dissolved in 10 mL of t-butanol and the solution wasbrought to reflux under argon. A freshly prepared and filtered solutionof silver benzoate (0.5 g, 2.18 mmol) in 3 mL of Et₃N was added dropwiseover 30 min via syringe. The reflux was continued for an additional 1 h.A small amount of decolorizing carbon was added and the reaction mixturewas filtered through celite. After evaporation of the filtrate, theresidue was chromatographed (silica, hexane:ethyl acetate (85:15)) togive 650 mg of R-t-butyl3-(cyclohexylmethyl)-3-t-butoxycarbonylaminopropionate, 141 (M+H)⁺:342.0.

A solution of 141 (650 mg, 1.90 mmol)) in 10 mL of TFA:DCM (1:1) wasstirred for 6 h at RT. The solvent was removed and the residue wastreated with Boc-anhydride in dioxan-aq NaOH to give 486 mg ofR-3-(cyclohexylmethyl)-3-t-butoxy carbonylamino-propionic acid, 142(M−H)⁺: 284.7.

A solution of 142 (284 mg, 1.0 mmol) and DIEA (258 mg, 2.0 mmol) in 5 mLof dry DMF was treated with HATU (380 mg, 1.0 mmol) at RT. After 5 min,4-cyanobenzylamine (132 mg, 1.0 mmol) was added and the reaction mixturewas stirred overnight at RT. Aqueous workup and chromatography (silicagel, hexane:ethyl acetate (1:3) gave 200 mg of the amide 143.

A solution of the amide 143 (200 mg, 0.5 mmol) in 10 mL of TFA:DCM (1:1)was stirred at RT for two days. The solvent was evaporated and theresidue was taken in 5 mL of DMF containing DIEA (258 mg, 2.0 mmol) and2,6-dichloro-4-(1-pyrrolyl)pyrimidine (107 mg, 0.5 mmol). After heatingovernight at 80° C., the reaction mixture was diluted with water and theproduct was extracted into ethyl acetate. The solvent was removed andthe residue was chromatographed (silica gel, hexane:ethyl acetate (1:3))to give 50 mg of the 2-(1-pyrrolyl)pyrimidine derivative and 58 mg ofthe 4-(1-pyrrolyl)pyrimidine compound 144, (M+H)⁺: 477.3

A solution of 144, (30 mg, 0.063 mmol) and 3-chlorobenzylamine (50 mg,0.35 mmol) in 2 mL of n-butanol was refluxed overnight. The solvent wasremoved and the residue was purified by chromatography (silica gel,hexane:ethyl acetate (1:3)) to give 4 mg of 145, (M+H)⁺: 582.3.

To 1,3-dithiane (6.2 g, 50.0 mmol) in 20 mL dry THF was added n-butyllithium (2.5M, 22 mL, 55.0 mmol) dropwise while cooling to −78° C. After30 minutes a solution of 2,4-dichloropyrimidine (10.0 g, 75 mmol) in 15mL dry THF was added dropwise. After 30 minutes the mixture was warmedto 0° and DDQ (12.5 g, 55.0 mmol) was added and allowed to warm to roomtemperature. After 1 hour the mixture was concentrated and the resultingresidue purified on a silica gel column, eluting with 3:7 EtOAc:hexanesto yield 2,4-dichloro-6-(2-dithianyl)pyrimidine as a light yellow oil(1.2 g, 5.5 mmol, 9%).

2,6-Dichloro-4-(1-pyrrolyl)pyrimidine was prepared as follows: A dry 500mL round bottom flask (oven-heated/argon cooled), was charged with 2.97g (74.34 mmol) of a 60% dispersion of sodium hydride in mineral oil. Theflask was purged with argon, and 200 mL of hexane were quickly added.The mixture was purged again, and stirred for 5-10 minutes. The stirringwas then stopped, and the sodium hydride was allowed to settle, at whichpoint the hexane was quickly decanted off. The mixture was purged withargon again and the rinsing was repeated, to ensure the reaction is freefrom the mineral oil suspension. Next, 200 mL of dry THF were injectedby syringe into the air-free mixture. The mixture was then cooled to 0°C., and connected to an oil-bubbler. Then 3.44 mL (49.60 mmol) ofpyrrole were injected into the mixture by syringe (vigorous bubblingoccurred as hydrogen evolved), and it was stirred for 1 hr. Finally, 10g (54.52 mmol) of 2,4,6-trichloropyrimidine were injected quickly intothe reaction mixture, and it was vigorously stirred overnight. Thereaction mixture was diluted with 200 mL of ethyl acetate and washedwith a solution of 14.5 g (75 mmol), of citric acid in 100 mL of water.The organic layer was extracted and dried with magnesium sulfate. Themixture was then concentrated down to give a brown, viscous material.The crude material was loaded relatively quickly onto a chromatographiccolumn (25″×3″), which was filled with 11¼″ silica gel. Elution wasstarted at 40:1 hexane/ether for about 2 L, and then the concentrationwas increased to 35:1 hexane/ether for about 4 L. The best TLC systemwas 9:1 hexane/ether. With that system, the four product spots could beseen: the top spot was the regio-isomer with the pyrrole substituted onthe 2-position of the pyrimidine, the second spot was unreactedpyrimidine, the third spot was the regioisomer with the pyrrolesubstituted at the 4-position (desired product), and the most polar spotwas a bis-addition product. Most of the desired product was separatedwith the column (2.5 g), but the remaining mixture with the bis-productwas recrystallized from hexane to give another 1.5 g. The total yieldwas 4 g (38%) of the white solid. ¹H NMR in CDCl₃: a 2H triplet at 6.42ppm (j=2.55 Hz), a 1H singlet at 7.16 ppm, and a 2H triplet at 7.48 ppm(J=2.55 Hz). In 9:1 hexane/ether, the R_(f)=0.37. This compound did notgive a mass spec signal.

The corresponding 2,6-difluoro-4-(1-pyrrolyl)pyrimidine is made inanalogous fashion from 2,4,6-trifluoropyrimidine. Both are useful asintermediates in the synthesis of B₁-BK antagonists of the invention. Animproved synthesis of 2,6-dichloro-4-(1-pyrrolyl)pyrimidine proceedsfrom 4-amino-2,6-dichloropyrimidine. A mixture of4-amino-2,6-dichloropyrimidine (5.0 g, 30.5 mmol) and2,5-dimethoxytetrahydrofuran (4.03 g, 30.5 mmol) in 100 mL of HOAc wasrefluxed for 2 hours. The reaction mixture was cooled to RT and pouredinto large quantity of water. The crude product was extracted into ethylacetate and the ethyl acetate layer was extracted successively withwater, aqueous NaHCO₃ and brine. The organic layer was dried (MgSO₄) andthe solvent was evaporated. The residue was purified by chromatography(silica gel, hexane:ethyl acetate (96:4) to provide 4.4 g (73%) of2,6-dichloro-4-(1-pyrrolyl) pyrimidine. ¹H NMR (CDCl₃): δ (ppm) 6.4(s,2H), 7.15 (s, 1H), 7.5 (s, 2H).

As described above, both the dichloro and the difluoro-intermediatesprovide mixtures of regioisomers when reacted with nucleophiles (cf. 144in Scheme 19). Although this is useful when both regioisomers aredesired, the route shown in Scheme 20 below provides a regioselectivesynthesis. According to Scheme 20,4-amino-6-chloro-2-methylthiopyrimidine 151 was reacted with 1equivalent of 2,5-dimethoxytetrahydrofuran in refluxing acetic acid toprovide 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152: ¹H NMR(CDCl₃) δ 2.75 (s,3H), 6.55 (d,2H), 7.05 (s,1H), 7.65 (d,2H). The6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152 is either (a)oxidized with 2.2 equivalents of m-chloroperoxybenzoic acid indichloromethane at 0° C. to provide6-chloro-2-methylsulfonyl-4-(1-pyrrolyl)pyrimidine 153 or (b) reactedwith 1 equivalent of the N-(p-cyanobenzyl)amide of cyclohexylalanine and1 equivalent of diisopropylethylamine in DMF at 80° C. to provide the2-methylthiopyrimidine 154. The oxidation and nucleophilic displacementsteps are then reversed [i.e. 153 is reacted according to (b) or 154 isreacted according to (a)] to provide the 2-methylsulfonylpyrimidine 155,which is dissolved in n-butanol saturated with ethylamine and heated ina sealed tube to produce 156.

Compounds of formulae

wherein X is —CN or halogen and L′ is —O—, —CH₂— or —N(CH₃)— are usefulintermediates for the preparation of compounds of preferred subgenera.Exemplary syntheses are shown below.

7-Cyano-4-chromanylamine was prepared as follows:

A dry, 250 mL round bottom flask was charged with 0.27 g (1.01 mmol) oftriphenylphosphine, 0.73 g (11.15 mmol) of potassium cyanide, 0.22 g(3.38 mmol) of zinc dust, and 0.38 g (0.51 mmol) ofbis(triphenylphosphine)nickel (II) bromide. The flask was then purgedwith argon, and an air-free solution of 3 g (10.14 mmol) of7-(((trifluoromethyl)sulfonyl)oxy)-4-chromanone [Koch et al., J. Org.Chem. 59, 1216 (1994)] in 40 ml of dry acetonitrile was introduced bysyringe. The solution was then heated at 60° C. for 3 hours, underargon. After cooling the solution to room temp, the solution was addedto an equal volume of water. The organic layer was extracted out, andthe aqueous layer was extracted several times with ethyl acetate andether. The combined organic phase was dried over magnesium sulfate,filtered and evaporated. The crude mixture was chromatographed using a20% ethyl acetate/hexane solvent system which yielded 1.3 g (76%) of7-cyano-4-chromanone as a white solid.

A dry, 200 mL round bottom flask was charged with 0.85 g (4.83 mmol) of7-(cyano)-4-chromanone, 3.72 g (48.30 mmol) of ammonium acetate, and0.91 g (14.45 mmol) of sodium cyanoborohydride. The flask was thenpurged with argon, and 30 mL of dry methanol was added by syringe. Thesolution was stirred at room temp for 48 hours. Concentrated HCl wasslowly added dropwise until pH<2 was reached. The methanol was thenevaporated by rotovap, and 30 mL of water was added to the suspension,which was then washed 3 times with ethyl acetate. The pH was thenbrought to >10 by adding sodium hydroxide pellets to the stirringaqueous mixture. Saturated sodium chloride was added, and the mixturewas then extracted several times with ether and ethyl acetate. Thecombined organic phase was dried over magnesium sulfate, filtered andevaporated to give 0.51 g (60%) of the desired7-(cyano)-4-chromanylamine as a pale yellow oil.

Characterization: The ¹H NMR in CDCl₃ (using a Varian Gemini 2000 modelNMR coupled to a 300 Mz Oxford Magnet) gave the following signals: abroad 2H singlet at 1.6 ppm, a 2H multiplet from 1.8-2.2 ppm, a 1Htriplet at 4.05 ppm (J=6 Mz), a 2H multiplet from 4.2-4.4 ppm, a 1Hsinglet at 7.1 ppm, a 2H doublet at 7.15 ppm (J=12 Mz), and a 2H doubletat 7.45 ppm (J=12 Mz).

A mixture of 4-chromanone (5 g, 33.7 mmol), hydroxylamine hydrochloride(2.34 g, 33.7 mmol and NaOAc (2.766 g, 33.7 mmol) in 100 mL of ethanolwas refluxed for 18 h. After cooling to RT, the solvent was removed andthe residue was partitioned between water and EtOAc. The EtOAc layer wasdried (MgSO₄), and the solvent was removed. The solid obtained wastriturated with hexane and filtered to provide 4.1 g of4-hydroxyiminochroman.

A solution of 4-hydroxyiminochroman (783 mg, 4.8 mmol) and triethylamine(484 mg, 4.8 mmol) in 120 mL of dry 1:1 DCM:hexane was cooled to −50° C.Chlorodiphenylphosphine (1.059 g, 4.8 mmol) was added via syringe andthe mixture was allowed to stir at −50° C. for 2 h. The mixture wascooled to −78° C. and filtered quickly under N₂ in a glove bag. Thefiltrate was evaporated and the crude N-diphenylphosphinylimine wastaken directly to the next step.

Formation of pre-modified borohydride: Under Ar atmosphere, in apre-cooled flask at 0° C. were placed 290 mg of NaBH₄ (7.5 mmol), 50 mLof CHCl₃, and 0.44 mL of EtOH (7.5 mmol) and 10 mL of tetrahydrofurfurylalcohol. The mixture was stirred for 3 h at 0° C.

Catalytic borohydride reduction: While maintaining solution ofpre-modified borohydride at 0° C., its solution was slowly added to thesolution of 37 mg of(1R,2R)-N,N′-Bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-1,2-diphenylethylenediaminatocobalt(II) (0.05 mmol, 1 mol %, TCI America) and the aforementionedphosphinylimine in 50 mL of CHCl₃. The stirring was continued for 4 h at0° C. The reaction was quenched by addition of saturated NH₄Cl andextracted with ether. The organic layer was dried (MgSO₄) and thesolvent was evaporated. The residue was purified by chromatography(silica, hexane:EtOAc, 1:3) to provide 300 mg of thediphenylphosphorylamine. (M+H)⁺: 350.1.

The diphenylphosphorylamine (300 mg, 0.86 mmol) was dissolved in MeOHsaturated with HCl gas and stirred overnight at RT. The solvent wasremoved and the residue was partitioned between water and ether. Theaqueous layer was basified and the liberated amine was extracted intoether. The ether layer was evaporated after drying (K₂CO₃) to provide(R)-4-aminochroman. The stereochemistry was assigned based on theliterature precedence (Sugi, K. D.; Nagata, T.; Mukaiyama, T. Chem.Lett. 1997, 493-494) and the optical purity was found to be >95% bychiral hplc. ¹H NMR (CDCl₃): δ 1.75 (bs, 2H, NH₂), δ 1.95-2.05 (m, 1H,CH₂CH₂O), δ 2.30-2.40 (m, 1H, CH₂CH₂O), δ 4.2 (t, 1H, CHNH₂), δ4.35-4.50 (m, 2H, CH₂O), δ 7.0 (d, 1H, ArH), δ 7.10 (t, 1H, ArH), δ 7.30(t, 1H, ArH), δ 7.50 (t, 1H, ArH).

According to Scheme 21 NaCNBH₃ (264 mg, 4.2 mmol) was added to a mixtureof 161 (340 mg, 1.99 mmol) [Almansa et al. Synth. Commun. 23, 2965(1993)] and NH₄OAc (1.5 g, 19.9 mmol) in dry methanol (30 ml), and thereaction was stirred at room temperature for a week. Removed solventunder vacuum. The residue was separated by silica gel chromatographycolumn with methanol/ammonium hydroxide/ethyl acetate (15:1:84) to give290 mg (84%) of 7-cyano-1,2,3,4-tetrahydronaphthylene-1-amine (162). NMR(CDCl₃): δ 1.66-2.12 (4H, CH₂x2), 2.78 (2H, CH₂), 4.0 (1H, CH), 7.37(1H, ArH), 7.44 (1H, ArH), 7.54 (1H, ArH).

To a solution of 7-cyano-1,2,3,4-tetrahydronaphthylene-1-amine (162)(290 mg, 1.69 mmol), and Et₃N (427 mg, 4.22 mmol) in DMF was added HATU(703 mg, 1.85 mmol) in one portion with stirring. The reaction wasstirred at room temperature overnight, then solvent was removed invacuo. Chromatographic purification with EtOAc/hexane (3:7) gave 145 mg(20%) of 163 and 151 mg (21%) of 164. The more polar diasteroisomer 163was converted into final compound 165 as described earlier.

2-Chloro-4-cyanobenzylamine was prepared as follows: To a stirredsolution of 2-chloro-4-cyanotoluene (10 g, 65.8 mmol) in dry carbontetrachloride (150 ml) were added N-bromosuccinimide (12.9 g, 72.4 mmol)and a catalytic amount of benzoyl peroxide. The reaction was refluxedunder stirring for 4 h and then filtered. Removed solvent from filtratein vacuo. The residue, 2-choro-4-cyanobenzyl bromide, was purified bychromatography with EtOAc/hexane.

To a stirred solution of 2-choro-4-cyanobenzyl bromide (6.9 g, 30.0mmol) in DMF (150 ml), was added sodium azide (2.0 g, 30 mmol) Thereaction was stirred overnight at room temperature, and then filtered.The DMF was removed from filtrate in vacuo. The residue was dissolved inEtOAc (300 ml), washed with water (200 ml×3), brine (200 ml×1), driedover sodium sulfate. Removed solvent in vacuo to give 5.8 g of raw2-choro-4-cyanobenzyl azide.

To a solution of 2-choro-4-cyanobenzyl azide (5.8 g, 30.1 mmol) inTHF/H₂O (3:1), was added triphenyl phosphine (12.3 g, 46.7 mmol). Thereaction was stirred at room temperature overnight, then neutralizedwith 1N sodium hydroxide, extracted with ethyl acetate (150 ml×3). Theorganic layer was dried over sodium sulfate, and then solvent wasremoved in vacuo. The product was purified by silica-gel chromatographycolumn with methanol/ammonia hydroxide/ethyl acetate (20:1:69) to give4.5 g (90%) of 2-chloro-4-cyanobenzylamine. NMR (CDCl₃): δ 4.0 (s, 2H,CH₂), 7.58 (d, 2H, HAr), 7.62 (s, 1H, HAr)

5-Aminomethylbenzofuroxan was prepared as follows:5-Bromomethylbenzofuroxan (2.13 g, 10 mmol, Gasco, A. M.; Errnondi, G.;Fruttero, R.; Gasco, A. Eur. J. Med. Chem 1996, 31, 3-10) was dissolvedin DMF and treated with potassium phthalimide (1.85 g, 10 mmol) at RTfor 15 h. After diluting with water, the product was filtered andcrystallized from EtOAc to provide 700 mg of the phthalimide. Thephthalimide was suspended in a mixture of 5 mL of ethanol and 5 mL of40% aq. methylamine, and the reaction mixture was stirred for 2 days atRT. The solvent was removed in vacuo and the residue was taken in ether.The ether layer was dried (MgSO₄) and the solvent was removed to yield110 mg of 5-aminomethylbenzofuroxan. ¹H NMR (CDCl₃): δ 1.8 (bs, 2H, NH₂)δ 4.1 (s, 2H, CH₂), δ 7.5 (d, 1H, ArH), δ 7.8-8.0 (m, 2H, ArH).

A solution of the nitrile 170 (100 mg, 0.2 mmol) and tributylstannylazide (133 mg, 0.4 mmol) in toluene was refluxed for two days. Thesolvent was evaporated and the residue was treated with 6 N HClovernight. After aqueous work up, the tetrazole 171 was purified bychromatography (silica, DCM:MeOH, 95:5). Yield: 35 mg (M+H)⁺: 527.3

According to Scheme 22, a solution of t-butyl ester ofD-cyclohexylalanine (2.7 g, 1187 mmol),2,4-dichloro-6-(1-pyrrolyl)pyrimidine (2.54 g, 11.87 mmol) anddiisopropylethylamine (1.53 g, 11.87 mmol) in DMF was heated to 90° C.for 24 h. After aqueous work up the crude product was purified bychromatography (silica, hexane:EtOAc, 9:1). The more polar spot was thedesired regioisomer 177. Yield 600 mg.

A solution of the regioisomer 177 (600 mg, 1.48 mmol) in 10 mL ofn-butanol containing 4 mL of cyclopropylamine was heated to 90° C. in asealed tube overnight. The solvent was removed and the product 178 waspurified by chromatography (silica, hexane:EtOAc, 9:1). Yield 486 mg.(M+H)⁺: 426.3.

A solution of the t-butylester 178 (486 mg, 1.14 mmol) in 10 mL of 1:1DCM:TFA was stirred overnight. The solvent was removed and the residuewas taken in EtOAc. The EtOAc layer was washed several times with waterand the solvent was removed in vacuo to provide 367 mg of the carboxylicacid. (M+H)⁺: 370.8.

4-Aminomethylpyridine N-oxide dihydrochloride (200 mg, 1.01 mmol) wassuspended in 3 mL of dry DMF and 200 mg of Et₃N (1.98 mmol) was added.The contents were stirred for 15 min. In the mean time, a solution ofthe carboxylic acid (100 mg, 0.27 mmol) from the previous step and Et₃N(300 mg, 2.97 mmol) in 5 mL of DMF was cooled in a ice bath and HATU(100 mg, 0.26 mmol) was added. After stirring for 3 min, aforementionedsolution of 4-aminomethylpyridine N-oxide was added and the stirring wascontinued for 3 days. Aqueous work up and chromatography (silica,EtOAc:MeOH, 85:15) gave 19 mg of 179. (M+H)⁺: 476.6.

A solution of the carboxylic acid 180 (197 mg, 0.57 mmol), HATU (218 mg,0.57 mmol) and Et₃N (172 mg, 1.70 mmol) in 5 mL of dry DMF was stirredfor 5 minutes. Then a solution of (R)-4-aminochroman (81 mg, 0.54 mmol)in 2 mL of dry DMF was added and the contents were stirred overnight.After aqueous work up, the residue was purified by chromatography(silica, hexane:EtOAc, 1:1) to provide 32 mg of 181. (M+H)⁺: 475.2.

According to Scheme 23, a mixture of2-methyl-2,3-dihydro-4-(1H)-isoquinolone (630 mg, 3.9 mmol, Nichols, D.E. et al.; WO9706799), ammonium acetate (3.0 g, 39 mmol) and NaCNBH₃(491 mg, 7.8 mmol) in 25 mL of dry methanol was stirred for 2 days atRT. The solvent was removed and the residue was acidified to pH 2 todestroy the excess NaCNBH₃. After basification with aq Na₂CO₃ to pH 10,the product was extracted into ether. The ether layer was dried (K₂CO₃)and the solvent was evaporated to provide 330 mg of the racemic4-amino-2-methyltetrahydroisoquinoline. ¹H NMR (CDCl₃): δ 2.20 (bs, 2H,NH₂), δ 2.60 (s, 3H, NCH₃), δ 2.90 (d, 2H, CHCH₂N), δ 3.55 (d, 1H,ArCH₂N), δ 3.90 (d, 1H, ArCH₂N), δ 4.15 (t, 1H, ArCHN), δ 7.20-7.60 (m,4H, ArH).

4-Amino-2-methyltetrahydroisoquinoline (320 mg, 1.97 mmol) was coupledwith N-(2-methylamino-4-(1-pyrrolyl)-6-pyrimidinyl)-D-cyclohexylalanine(180)(237 mg, 0.69 mmol) using HATU as described earlier. After aqueouswork up, the residue was purified by chromatography (silica, EtOAc). Thediastereomer 183 with higher R_(f) was assigned R-stereochemistry at thebenzylic center based on its biological activity, yield: 78 mg, (M+H)⁺:488.2. The more polar isomer was assigned S-stereochemistry, yield: 71mg, (M+H)⁺: 488.1.

According to Scheme 24, HATU (1.165 g, 3.07 mmol) was added at 0° C. toa solution of N-Boc-D-cyclohexylalanine (831 mg, 3.07 mmol) and Et₃N(620 mg, 6.14 mmol) in 15 mL of dry DMF. After stirring for 2 min,7-cyano-4-chromanylamine (540 mg, 3.068 mmol) was added and the stirringwas continued overnight. After aqueous work up and chromatography(silica, hexane:EtOAc, 70:30), 420 mg of the less polar diastereomer 186(M+H⁺: 427.8), and 380 mg of the more polar diastereomermer 185 (M+H⁺:427.8) were obtained. A solution of the more polar diastereomer 185 (380mg, 0.89 mmol) was stirred in DCM:TFA (1:1) overnight at RT. Aqueouswork up at basic pH provided 270 mg of the primary amine 187.

A mixture of amine 187 (270 mg, 0.82 mmol), DIEA (106 mg, 0.82 mmol) and2,4-dichloro-6-(1-pyrrolyl)pyrimidine (175 mg, 0.82 mmol) in DMF washeated to 90° C. overnight. Aqueous work up and chromatography (silica,hexane:EtOAc, 1:1) provided 120 mg of the less polar regioisomer and 96mg of the more polar desired regioisomer 188.A solution of the more polar regioisomer 188 (58 mg, 0.11 mmol) inn-butanol was saturated with methylamine at −20° C. The solution wasthen heated to 90° C. in a sealed tube overnight. After cooling, thesolvent was removed in vacuo and the residue was purified bychromatography (silica, hexane:EtOAc, 1:1) to provide 25 mg of 189.(M+H)⁺: 500.3.

4-Amino-7-chloro-2-methyltetrahydroisoquinoline was prepared as shownabove in Scheme 25: To a stirred solution of methyl4-chloro-2-methylbenzoate (8.9 g, 48.2 mmol) in dry carbon tetrachloride(150 ml) were added N-bromosuccinimide (9.4 g, 53.0 mmol) and acatalytic amount of benzoyl peroxide. The reaction was refluxed understirring for 12 h and then filtered. Removed solvent from filtrate invacuo to give 12.0 g of the crude benzyl bromide. NMR(deuteriochloroform): δ 3.92 (s, 3H, CH₃), 4.92 (s, 2H, CH₂), 7.34 (d,1H, ArH), 7.46 (s, 1H, ArH), 7.79 (d, 1H, ArH).

To a mixture of sarcosine ethyl ester hydrochloride (7.4 g, 63 mmol),sodium carbonate (8.2 g, 77.4 mmol), and toluene (300 ml) was added asolution of the benzyl bromide (12.0 g, 45.5 mmol) in toluene at roomtemperature. The reaction was heated at 85° C. with stirring for 12 h,cooled to room temperature, and then filtered. The filtrate wascollected and extracted with 3N HCl (150 ml×3). The aqueous layer wascollected, basified with saturated Na₂CO₃ solution, and extracted withether (150 ml×3). To remove the solvent from the organic solution give8.4 g (61%) of 190. NMR (CDCl₃): δ 1.30 (m, 3H, CH₃), 2.38 (s, 3H, CH₃),3.3 (s, 2H, CH₂), 3.86 (s, 3H, CH₃), 4.0 (S, 2H, CH₂), 4.18 (m, 2H,CH₂), 7.26 (D, 1H, ArH), 7.60 (s, 1H, ArH), 7.74 (D, 1H, ArH).

Freshly cut sodium (0.84 g, 36.3 mmol) was added to absolute methanol(30 ml) under argon. The reaction was refluxed until sodium metaldisappeared. A solution of 190 (8.4 g, 27.9 mmol) in dry toluene (150ml) was added slowly. The mixture was heated at reflux to remove extramethanol via a Dean Stark trap. Fresh dry toluene (150 ml) was added andrefluxed for 2 h. After cooling, solvent was removed under vacuum. Theremains dissolved in ethanol (150 ml) were treated with 2N NaOH (250ml). It was refluxed for 1.5 h, cooled to room temperature, acidifiedwith 8N HCl, and then refluxed for 2.5 h. The reaction mixture wascooled to room temperature, basified with 6N NaOH, extracted withmethylene chloride (150 ml×3). The organic layer was dried over Na₂SO₄.The solvent was removed in vacuo. The residue was purified bychromatography with EtOAc/Hexane (1:1) to give 1.82 g (31%) of theisoquinolone. NMR (CDCl₃): δ 2.46 (s, 3H, CH₃), 3.3 (s, 2H, CH₂), 3.7(s, 2H, CH₂), 7.22 (d, 1H, ArH), 7.3 (s, 1H, ArH), 7.96 (d, 1H, ArH).

To a mixture of compound tetrahydroisoquinolone (1.8 g, 9.3 mmol) andNH₄OAc (7.1 g, 9.3 mmol) in dry methanol (80 ml) was added NaCNBH₃ (2.9g, 46.4 mmol). The reaction was stirred at room temperature for 3 days.Removed solvent under vacuum. The residue was separated by silica gelchromatography column with methanol/ammonia hydroxide/ethyl acetate(20:1:79) to give 1.1 g (60%) of4-Amino-7-chloro-2-methyltetrahydroisoquinoline. NMR (CDCl₃): δ 1.7 (2H,CH₂), 2.4 (3H, CH₃), 2.66 (2H, CH₂), 7.0(1H, ArH), 7.2 (1H, ArH), 7.28(1H, ArH).

All of the compounds shown in the tables below have been examined byhigh resolution mass spectrometry and have provided MH⁺ ions andfragments consistent with the structures shown.

Bioassays

Tissues are taken from New Zealand white rabbits (1.5-2.5 kg) and DuncanHartley guinea pigs (250-350 g) of either sex, killed by stunning andexsanguination. Human umbilical cords are obtained after spontaneousdelivery at term. The rabbit jugular vein (RbJV) and the guinea pigileum (GPI), are two preparations containing B₂ receptors. The rabbitaorta (RbA) contains B₁ receptors, and the human umbilical vein (HUV) isa mixed preparation containing both B₁ and B₂ receptors. Helical stripsof RbJV, treated with 1 μmol/L of captopril to avoid peptidedegradation, are prepared according to Gaudreau et al. [Can. J.Physical. Pharmacol. 59, 371-379 (1981)] Helical strips of RbA devoid ofendothelium are prepared according to Furchgott and Bhadrakom. [J.Pharacol. Exp. Ther. 108, 124-143 (1953)] Longitudinal segments of GPIare prepared with the procedure described by Rang [Brit. J. Pharmacol.22, 356-365 (1964)]. Helical strips of HUV are prepared according toGobeil et al. [Brit. J. Pharmacol. 118, 289-294 (1996)]. Unlessotherwise indicated below, the tissues are suspended in 10-mL organbaths containing warm (37° C.), oxygenated (95% O₂-5% CO₂) Krebssolution of the following composition in mmol/L; NaCl: 118.1; KCl: 4.7;CaCl₂6H₂O: 2.5; KH₂PO₄: 1.2; MgSO₄7H₂O:1.18; NAHCO₃: 25.0 and D-Glucose:5.5. The RbA are stretched with an initial tension of 2 g, whereas theRbJV and the GPI are loaded with 0.5 g. Changes of tension produced bythe various agents are measured with Grass isometric transducers (modelFT 03C, Grass Instrument Co., Quincy, Mass.). Myotropic contractions aredisplayed on a polygraph. Before testing the drugs, the tissues areallowed to equilibrate for 60-120 minutes, during which time the tissuesare repeatedly washed and the tension readjusted every 15 min.

At the beginning of each experiment, a submaximal dose of bradykinin(BK) (9 mmol/L), is applied repeatedly on the RbJV, the GPI or the HUVto ensure that tissues responded with stable contractions. In the RbA,the B₁ preparation whose response has been shown to increase during theincubation in vitro, desArg⁹ K (550 nmol/L) are applied 1, 3 and 6 hafter the equilibration period, in order to monitor the progressiveincrease of sensitivity of the tissue which generally reaches themaximum after 3-6 h.

Repeated applications of a single and double concentration of BK (onRbJV, GPI and HUV) and of desArg⁹BK (RbA and HUV) are made in theabsence and in presence of the test compounds to evaluate their apparentaffinities as antagonists, in terms of pA₂ (−log₁₀ of the molarconcentration of antagonist that reduces the effect of a doubleconcentration of agonist to that of a single one). The antagonists areapplied 10 min before measuring the myotropic effects of either BK (theB₂ receptor agonist) or desArg⁹BK (the B₁ receptor agonist).Pharmacological assays on the HUV (a mixed B₁ and B₂ receptorpreparation) are done in presence of either HOE140 (400 mmol/L) (apotent B₂ receptor antagonist) or Lys[Leu⁸]des Arg⁹BK (1 μmol/L) (apotent B₁ receptor antagonist) (applied 10 min prior to the testedagents) to study the B₁ and the B₂ receptors, respectively. All kininantagonists are initially applied to tissues at concentration of 10μg/mL to measure their potential agonistic activities (α^(E)) incomparison with BK (in the B₂ receptor preparations) or desArg⁹BK (inthe B₁ receptor preparations). The compounds of the present inventionexhibit inhibition at very low concentrations only when tested in humanor primate systems; thus the foregoing (and following) tests in rabbitand rodent tissues are useful only for demonstrating lack of undesiredeffects on other receptors than B₁ and in other tissues than human. Inorder to determine the potency of compounds of the invention, thosetests that employ rabbit and rodent tissues are modified to employ humanand primate tissues, as well known to persons in the art.

Streptozotocin has been extensively used to produce type I diabetes inanimals. This experimental disease is characterized by a mildinflammatory reaction in the Langerhans islets. Male C57 L/K₃ mdb miceare injected with streptozotocin (40 mg/kg) for 5 consecutive days. Thekinin B₁ receptor antagonists are injected subcutaneously to STZ mice at300 μg/Kg bw twice a day and 500 μg/Kg per day, respectively. Treatmentwith antagonists is started 3 days after STZ and lasts for 10 days.Plasma glucose is determined by the glucose oxidase method, and urinarysamples are assayed at 13 days for proteins, nitrites and kallikreins.Diabetic mice show hyperglycemia and increased diuresis, markedproteinuria and increased excretion of nitrites and kallikreins. B₂receptor antagonists reduce water and protein excretion, compared to STZgroup; STZ mice treated with B₁ receptor antagonists show normalglycemia and normalization of diuresis, protein, nitrite and kallikreinexcretion.

The contractile response of the portal vein (a suitable preparation forB₁-BK studies) obtained from untreated 8-week old spontaneouslyhypertensive rats (SHR), is exaggerated and susceptible to enhancedcapillary hydrostatic pressure and plasma leakage. Desendothelializedportal vein segments obtained from SHR are mounted in organ bathscontaining a Krebs solution for isometric contraction studies (baselinetension: 0.5 g). Test compounds are administered on portal vein segmentsobtained from normal rats and SHR, to establish dose-response curves.

Bradykinin B₁ receptor binding in human tissue is determined by themethod of Levesque et al. [Immunopharmacology 29, 141-147 (1995); andImmunopharmacology 28, 1-7 (1994)]. Human embryonic fibroblast cellsfrom the IMR-90 line (available from ATCC as CCL 186) are grown inminimal essential medium as described by Menke et al [J. Biol. Chem.269, 21583-21586 (1994)]. After 24 hours, the culture medium is replacedwith low serum media (0.4% fetal bovine serum) containing recombinanthuman IL-1β (0.25 mg/mL) and the cells are further incubated for 4-5hours. The cells are harvested with trypsin and resuspended in Medium11995-065 (Gibco, Gaithersburg, Md., USA) supplemented with L-glutamine,non-essential amino acids and 10% fetal bovine serum at 1.7×10⁶cells/mL. Thirty microliters of the cell suspension in a plate is mixedwith 10 μL of straight buffer [1 L of Medium 199 (Gibco, Gaithersburg,Md., USA), 25 mL of HEPES buffer, 1 g bovine serum albumin 3 μMamastatin, 1 μM captopril and 1 μM phosphoramidon (Sigma, St. Louis,Mo., USA)] or 10 μL of buffer containing 5 to 50 μM B₁-BK antagonist and10 μL of 11 μM ³H-desArg¹⁰-kallidin. The plates are incubated at roomtemperature for about 1.5 hours. After incubation, each well is washedwith 150 μL of ice-cold PBS at pH 2.4. The contents are transferred to aglass fiber plate that has been pretreated with polyethyleneimine andthe plate is air dried. Scintillation fluid is added and the resultingsolution is counted in a gamma counter for 10 minutes. Statisticalanalysis is performed on the saturation curves. Scatchard regressionparameters are calculated from the mean saturation data using a computerprogram (Tallarida and Murray, 1987). The resulting B_(max) and K_(d)values and their respective SEM are compared in order to assessstatistical differences using Student's t-test. The compounds of theinvention exhibit Ki's below 10 μM. Specific examples of compounds whichhave been synthesized and tested are shown in Tables 1 and 2. Thosecompounds in Table 1 exhibited K_(i)'s of 1 to 500 nM; those in Table 2exhibited K_(i)'s of 501 nM to 10 μM.

Potency and efficacy in human tissue are assessed as follows: Humanumbilical cords are obtained within 24 hours following normal deliveriesand are stored in physiological salt solution (PSS) at 4° C. Thecomposition of the PSS is as follows: 118 mM NaCl, 4.6 mM KCl, 1.2 mMKH₂PO₄, 1.2 mM MgSO₄, 2.5 mM CaCl₂, 0.026 mM CaNa₂EDTA, 10 mM glucose,and 24.8 mM NaHCO₃. The umbilical vein is carefully dissected and placedin ice-cold, PSS, which is continuously aerated with 95% O₂/5% CO₂ tomaintain pH at 7.4. Excess connective tissue is removed, and rings 2-3mm in length are prepared. The rings are mounted between stainless steelwires in water-jacketed tissue baths for measuring contractile function.The rings are attached to a force-displacement transducer for measuringtension development. The baths contain 15 mL of oxygenated PSSmaintained at 37° C.

After mounting, resting tension is adjusted to 1.0 g and the rings areequilibrated for 60 minutes before beginning the experiment. The tissuebaths are rinsed with fresh PSS 30 min and 60 min after mounting therings. Following each rinse, the resting tension is adjusted to 1.0 g.After the equilibration period, the rings are depolarized by addingincreasing concentrations of KCl to the tissue bath until a maximumincrease in tension is obtained. The bath is rinsed with fresh PSS, andthe resting tension readjusted to 1.0 g. the response to KCl is repeatedtwo additional times at 30-min intervals. The maximum increases intension obtained following the second and third assessments of theresponse to KCl are averaged. The value is used to normalize the directresponse to the test compound, and also the response to a referencebradykinin receptor agonist.

Evaluating an Antagonist Effect: After assessing the responses to KCl,the test compound is added to the tissue bath. Thirty minutes later, thefollowing concentrations of desArg¹⁰ Kallidin are added to the tissuebath: 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 nM. The response to eachconcentration of desArg¹⁰ Kallidin is normalized as a percentage of themaximum constrictor response to KCl.Evaluating a Direct Effect: After assessing the responses to KCl, thefollowing concentrations of the test compound are added to the tissuebath: 1, 3, 10, 30, 100, 300, 1000, 3000 and 10000 nM. Alternatively, anequivalent volume of the vehicle used to solubilize the test compound isadded to the tissue baths. Each new concentration is added to the bathafter the response to the previous concentration has reachedequilibrium. If no response is obtained, the next concentration of testcompound is added to the bath 15 min after the previous concentration.

While it may be possible for the compounds of formula (I) to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof,together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients, as discussedbelow. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Pharmaceutical formulations, particularly topical formulations, mayadditionally comprise steroidal anti-inflammatory drugs, which mayinclude but are not limited to alclometasone dipropionate, amcinonide,beclamethasone dipropionate, betamethasone benzoate, betamethasonedipropionate, betamethasone valerate, budesonide, clobetasol propionate,clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate,diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide,fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolonepreparations, fluprednidene acetate, flurandrenolone, halcinonide,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,methylprednisolone acetate, mometasone furoate and triamcinoloneacetonide.

Pharmaceutical formulations may also additionally comprise steroidalanti-inflammatory drugs for oral administration. These may include butare not limited to finasteride, betamethasone and hydrocortisone.

Alternatively or additionally, pharmaceutical formulations mayadditionally comprise nonsteroidal anti-inflammatory drugs (NSAIDS),which may include but are not limited to aminoarylcarboxylic acids(fenamic acid NSAIDs), arylacetic acids, arylbutyric acids such asfenbufen, arylpropionic acids (profens), pyrazoles such as epirizole,pyrazolones such as phenylbutazone, salicylic acids such as aspirin,oxicams and other compound classes that may be considered as NSAIDSincluding leucotriene antagonists. These formulations exhibit both theadditive effects of the individual components and synergistic effectsfrom blocking of multiple pathways in the pain and inflammation pathway.

Propionic acid NSAIDs are non-narcotic analgesics/nonsteroidalantiinflammatory drugs having a free —CH(CH₃)COOH group, whichoptionally can be in the form of a pharmaceutically acceptable saltgroup, e.g., —CH(CH₃)COO⁻Na⁺. The propionic acid side chain is typicallyattached directly or via a carbonyl function to a ring system,preferably to an aromatic ring system. Exemplary propionic acid NSAIDSinclude: ibuprofen, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, pirprofen, carpofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, fluprofen,and bucloxic acid. Structurally related propionic acid derivativeshaving similar analgesic and antiinflammatory properties are alsointended to be included in this group. Profens, as well as NSAIDs fromother classes, may exhibit optical isomerism. The invention contemplatesthe use of pure enantiomers and mixtures of enantiomers, includingracemic mixtures, although the use of the substantially optically pureeutomer will generally be preferred.

Acetic acid NSAIDs are non-narcotic analgesics/nonsteroidalantiinflammatory drugs having a free —CH₂COOH group (which optionallycan be in the form of a pharmaceutically acceptable salt group, e.g.—CH₂COO⁻Na⁺, typically attached directly to a ring system, preferably toan aromatic or heteroaromatic ring system. Exemplary acetic acid NSAIDSinclude: ketorolac, indomethacin, sulindac, tolmetin, zomepirac,diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, andfenclozic acid. Structurally related acetic acid derivatives havingsimilar analgesic and antiinflammatory properties are also intended tobe encompassed by this group.

Fenamic acid NSAIDs are non-narcotic analgesics/nonsteroidalantiinflammatory drugs having a substituted N-phenylanthranilic acidstructure. Exemplary fenamic acid derivatives include mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid.

Biphenylcarboxylic acid NSAIDs are non-narcotic analgesics/nonsteroidalantiinflammatory drugs incorporating the basic structure of abiphenylcarboxylic acid. Exemplary biphenyl-carboxylic acid NSAIDsinclude diflunisal and flufenisal.

Oxicam NSAIDs are N-aryl derivatives of 4-hydroxyl-1,2-benzothiazine1,1-dioxide-3-carboxamide. Exemplary oxicam NSAIDs are piroxicam,tenoxicam sudoxicam and isoxicam.

Pharmaceutical formulations may also include cyclo-oxygenase (COX)inhibitors (including arylpropionic acids such as ibuprofen andsalicylic acids such as aspirin), selective cyclooxygenase-1 (COX-1)inhibitors or selective cyclo-oxygenase-2 (COX-2) inhibitors such asrofecoxib or celecoxib. These formulations also exhibit both theadditive effects of the individual components and synergistic effectsfrom blocking of multiple pathways in the pain and inflammation pathway.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. When thecompounds of the present invention are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Suitable pharmaceutically acceptable acid addition saltsfor the compounds of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. When the compounds contain anacidic side chain, suitable pharmaceutically acceptable base additionsalts for the compounds of the present invention include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. A tablet may be made bycompression or moulding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with a binder, lubricant, inertdiluent, lubricating, surface active or dispersing agent. Molded tabletsmay be made by molding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and may be formulated so as to providesustained, delayed or controlled release of the active ingredienttherein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient. Formulations for parenteraladministration also include aqueous and non-aqueous sterile suspensions,which may include suspending agents and thickening agents. Theformulations may be presented in unit-dose of multi-dose containers, forexample sealed ampules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of a sterile liquidcarrier, for example saline, phosphate-buffered saline (PBS) or thelike, immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia. It should beunderstood that in addition to the ingredients particularly mentionedabove, the formulations of this invention may include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavoring agents.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbelow recited, or an appropriate fraction thereof, of theactive ingredient. The compounds of the invention may be administeredorally or via injection at a dose from 0.001 to 2500 mg/kg per day. Thedose range for adult humans is generally from 0.005 mg to 10 g/day.Tablets or other forms of presentation provided in discrete units mayconveniently contain an amount of compound of the invention which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The compounds of formula (I) are preferably administered orally or byinjection (intravenous or subcutaneous). The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. However, the dose employed will depend on a number offactors, including the age and sex of the patient, the precise disorderbeing treated, and its severity. Also, the route of administration mayvary depending on the condition and its severity.

EXAMPLE 1 Aqueous Suspension for Injection

A suspending vehicle is prepared from the following materials:

Polyethylene glycol 4000 30 gm. Potassium chloride 11.2 gm. Polysorbate80 2 gm. Methylparaben 0.2 gm. Water for injection q.s. 1000 mL.

The parabens are added to a major portion of the water and are dissolvedtherein by stirring and heating to 65° C. The resulting solution iscooled to room temperature and the remainder of the ingredients areadded and dissolved. The balance of the water to make up the requiredvolume is then added and the solution sterilized by filtration. Thesterile vehicle thus prepared is then mixed with 3 gm of B₁-BK inhibitorof the invention (e.g. compound 10), which has been previously reducedto a particle size less than about 10 microns and sterilized withethylene oxide gas. This mixture may then be mixed, optionally, with 5gm of an antiinflammatory (e.g. hydrocortisone), which has beenpreviously reduced to a particle size less than about 10 microns andsterilized with ethylene oxide gas. The mixture is passed through asterilized colloid mill and filled under aseptic conditions into sterilecontainers which are then sealed.

EXAMPLE 2 Water-washable Cream

The following ingredients are formulated:

Ingredients Percent w/w Hydrocortisone acetate 0.025 Compound 10 0.025Mineral Oil 6.0 Petrolatum 15.0 Polyethylene glycol 1000 monocetyl ether1.8 Cetostearyl alcohol 7.2 Chlorocresol 0.1 Distilled water to produce100 parts by weight

The cortisone and B₁-BK antagonist 10 are ball-milled with a littlemineral oil to a particle size of less than 5 microns. The water isheated to boiling, the chlorocresol added and the solution then cooledto 65° C. Then the petrolatum, cetostearyl alcohol and polyethyleneglycol ether are mixed together while heating to 65° C. The milledsteroid suspension is then added to the melt rinsing the container withmineral oil. The active ingredient oily phase thus prepared is added at60° C. to the chlorocresol aqueous phase at 65° C. The mixture isstirred rapidly while cooling past the gelling point (40°-45° C.) andthe stirring is continued at a speed sufficiently slow to permit thecream to set. The water-washable cream may be used in the treatment ofdermatoses using either the open (without occlusion) or occlusive methodof drug application. EXAMPLE 3

Topical Ointment

Hydrocortisone acetate 0.05 gm  Compound 10 1.00 gm. Chloroxine 1.00 gm.Propylene Glycol 7.00 gm. Glyceryl monostearate 5.00 gm. with emulsifierWhite petrolatum q.s.a.d. 100.00 gm. 

Heat the propylene glycol to 55° C. Add hydrocortisone acetate, compound10, and chloroxine and mix well. Add the remaining ingredients and mixuntil melted. Remove from heat and mix slowly until cooled to 45° C.,then homogenize.

EXAMPLE 4 Tablets

Composition per tablet: compound 10   30 mg Precipitated calciumcarbonate   50 mg Corn Starch   40 mg Lactose  73.4 mgHydroxypropylcellulose    6 mg Magnesium stearate  (0.05 mL) Total 200.0mg

Compound 10, precipitated calcium carbonate, corn starch, lactose andhydroxypropylcellulose are mixed together, water is added, and themixture is kneaded, then dried in vacuum at 40° C. for 16 hours, groundin a mortar and passed through a 16-mesh sieve to give granules. To thisis added magnesium stearate and the resultant mixture is made up intotablets each weighing 200 mg on a rotary tableting machine.

TABLE 1 STRUCTURE Identifier

978163

645199

283326

309799

322835

697855

999865

294578

182337

214748

531746

835218

146684

020990

091083

680690

022238

292412

337677

596668

680800

919044

234134

120005

247664

115870

179617

249564

109900

240885

003493

042066

300801

730438

207077

708899

568105

422025

323150

566861

234930

048598

000753

406301

320650

189058

139629

751675

474275

172231

726261

751597

696705

525792

848872

081258

599337

579244

271260 840374

278223

020166

683298

595832

306362

464797

391849

056753

778772

190226

481412

862426

417305

311513

678923

333652

614669

700597

533089

912433

292686

082240

296547

917474

923768

482006

040264

917511

559426

552742

489595

045950

070576

251669

167032

190237

307763

832836

310187

369774

833980

191099

087621

288176

630450

714119

124640

506593

340407

036412

884068

768710

207224

221378

183701

389573

936359

019738

736433

604361

125906

638954

186809

614977

614250

788826

078208

487103

542442

634762

191433

319591

841733

814072

235566

959191

812971

037353

105995

629668

159661

081752

696652

312958

757098

223929

930464

391100

337128

185383

769887

532528

817699

702309

888316

578730

917717

326011

794377

905178

573817

598738

857482

663495

991312

225992

926424

339394

781549

566540

584062

615004

098519

815097

360639

828037

972282

080030

811358

097881

270821

655480

713653

091950

014922

556200

936852

167307

218245

424569

307763

532528

997039

599337

389573

919044

091217

813326

592843

053116

416383

762112

788965

956568

592995

642706

916924

406896

463621

103379

073408

815097

115870

579244

551184

194859

934834

762112

818697

005195

018412

030876

031155

054101

066361

095564

109718

129311

139299

154213

167307

178323

192258

198950

215301

215318

218245

222477

237360

307742

309001

312972

327891

334878

337854

347952

360912

368057

380712

395117

410204

412904

414904

424569

426754

442350

444713

452881

456816

466502

492190

512937

556200

447846

572620

588712

596982

603364

662666

670583

698545

708752

724612

739750

797241

817552

824754

835714

847939

859657

881196

919420

936852

960142

968882

993416

339883

428825

TABLE 2 STRUCTURE Identifier

459868

397897

703779

966132

276572

748623

770799

474269

715066

884607

387845

334057

703736

169968

405907

577561

651408

834615

836641

419551

830601

555804

031557

085311

340085

574878

906426

396104

404682

637763

006801

309888

889134

888340

407599

458001

214357

324675

622414

193177

979425

054066

170440

129647

327168

600629

984213

832914

065864

727448

429933

603335

826751

844156

930501

963106

583734

059809

916267

295459

386842

855317

862111

156360

808880

980203

726338

257040

327989

864091

630878

040296

027665

212579

557004

263415

302927

674216

034480

284784

390534

541410

306344

892732

209284

906426

774868

626899

367587

240936

075438

006518

026511

085374

107571

242518

25037

251559

291582

343424

357720

364637

378606

383670

567456

588918

621206

626899

629441

640538

672975

687899

709833

730697

733184

774868

1828493

866399

867894

870562

917930

928221

953837

480759

1. A compound of formula

wherein: A is A¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom imidazolyl, methylimidazolyl, pyrrolyl, methylpyrrolyl, pyrazolyl,methylpyrazolyl, hydroxymethylimidazolyl,(dimethylaminomethyl)imidazolyl, furanyl, methylfuranyl, thienyl,oxazolyl, thiazolyl, pyridinyl, quinolinyl, 1-methylpyrimidin-2-onyl,phenyl, fluorophenyl, hydroxymethyl, tetrahydropyranyloxymethyl,imidazolylmethyl, pyrrolylmethyl, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl, orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; m is zeroor one; and n is zero or one, with the proviso that when A is A², m andn cannot both be zero.
 2. A 4-pyrimidinamine according to claim 1wherein: Q is chosen from pyrrol-1-yl, imidazol-1-yl, furan-3-yl,2-methylimidazol-1-yl and 4-methylimidazol-1-yl; A is R⁴R⁵N—C(O)—; W isCl, NHR⁹, N(CH₃)R⁹, OR⁸, SR⁸, R⁸, morpholin-4-yl;

R¹ is chosen from alkyl, cycloalkyl, C₁-C₃-alkylaryl,C₁-C₃-alkylcycloalkyl, C₁-C₃-alkylheterocyclyl, C₁-C₃-alkylheteroarylR², R³ and R⁵ are H; R⁸ is C₁-C₄-alkylaryl; R⁹ is chosen from hydrogen,alkyl, substituted alkyl, (C₁-C₄)-alkoxy, C₁-C₄-alkylcycloalkyl,C₁-C₄-alkylaryl, heterocyclyl, C₁-C₄-alkylheteroaryl,C₁-C₄-alkylheterocyclyl; and m and n are zero.
 3. A 4-pyrimidinamineaccording to claim 2 wherein W is NHR⁹ and R⁹ is chosen from hydrogen;methyl; ethyl; 2,2,2-trifluoroethyl; allyl; cyclopropyl; 2-cyanoethyl;propargyl; methoxy; methoxyethyl; cyclopropyl; cyclopropylmethyl;(methylthio)ethyl; 3-methoxypropyl; 3-pyridyl; 2-(3-pyridyl)ethyl;2-(2-pyridyl)ethyl; 3-pyridylmethyl; 4-pyridylmethyl;4-pyridylmethyl-N-oxide; 2-pyridazinylmethyl; sulfolan-3-yl;3-tetrahydrofuranyl; 2-tetrahydrofuranylmethyl; 3-(1-imidazolyl)propyl;1-t-butoxycarbonyl-4-piperidinyl;1-t-butoxycarbonyl-4-piperidinylmethyl; 2-(hydroxyimino)propyl;2-(methoxyimino)propyl; 2-oxo-1-propyl; and

wherein R¹⁴ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,OH, SO₂CH₃, N(CH₃)₂ and COOH; R¹⁵ is chosen from H, OCH₃ and Cl; and pis 1 or
 2. 4. A 4-pyrimidinamine according to claim 2 wherein W is

and R¹² is t-butoxycarbonyl, methoxyacetyl or phenyl.
 5. A compound offormula

wherein: A is

R¹ is chosen from n-butyl; cyclohexylmethyl; cyclopentylmethyl;2-methylpropyl; 3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl;benzyl; 2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl;4-chlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and1,1-dimethylethyl; R² and R³ are H; Q is imidazolyl or pyrrolyl; R⁶ isaryl; R⁴ is chosen from H, aryl, heteroaryl, C₁-C₄-alkyl substitutedwith from one to three aryl or heteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁷ is aryl or C₁-C₃-alkylaryl; W is NHR⁹; and R⁹is alkyl, cycloalkyl or

wherein R¹⁴ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁵ is chosen from H, OCH₃ and Cl; m iszero or one; and n is zero or one, with the proviso that when A ischosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—, m and n cannot bothbe zero.
 6. A compound of formula

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isR⁴R⁵N—C(O)—; Q is chosen from heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from isopropyl; n-butyl; cyclohexylmethyl;cyclopentylmethyl; naphthylmethyl; cyclohexylethyl; 2-methylpropyl;3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl; benzyl;2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl; 4-methoxybenzyl;4-chlorobenzyl; 3,4-dichlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl;4-pyranyl and 1,1-dimethylethyl; R², R³ and R⁵ are H; R⁴ is chosen fromH, aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three arylor heteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁷ is aryl or C₁-C₃-alkylaryl; R⁸ is chosen fromalkyl, aryl, heteroaryl, substituted alkyl, C₁-C₄-alkylaryl,C₁-C₄-alkylheterocyclyl and C₁-C₄-alkylheteroaryl; R⁹ is chosen from H,alkyl, alkenyl, substituted alkyl, cycloalkyl, aryl, alkoxy, heteroaryl,fluoroalkyl, C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl,(C₁-C₄-alkoxycarbonyl)alkyl, (C₁-C₄-alkylthio)alkyl, heterocyclyl,C₁-C₄-alkylheterocyclyl, C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰is H or C₁-C₃-alkyl, or R⁹ and R¹⁰ taken together may form a 5- to7-membered ring structure optionally containing O, S, SO, SO₂ or NR¹²,said ring optionally substituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ isaryl; R¹² is chosen from H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyland aryl; R¹³ is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; mis zero or one; and n is zero or one, with the proviso that when A ischosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—, m and n cannot bothbe zero.
 7. A pyrimidine according to claim 6 wherein: R⁴ is pyridinyl,pyridinylmethyl, tetrahydronaphthalenyl, indanylmethyl, furanylmethyl,substituted phenyl, or

R¹⁶ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, CH₃, COOCH₃, OCH₃,SO₂CH₃, SOCH₃, N(CH₃)₂, tetrazol-5-yl, CONH₂, C(═NOH)NH₂ and COOH; andR¹⁷ is chosen from H, OCH₃, F and Cl.
 8. A pyrimidine according to claim6 wherein R⁴ is

one of J¹ and J² is H and the other is H, Cl or CN and G is chosen from—CH₂—, —CH₂CH₂—, —OCH₂—, —O— and —CH₂N(lower alkyl)-.
 9. A compound offormula

wherein: A is A¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl; orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 10. A 2-pyrimidinamine according to claim 9 wherein Q ischosen from imidazolyl, pyrrolyl, pyridinyl, fluorophenyl and 2-thienyl.11. A 2-pyrimidinamine according to claim 10 wherein A is R⁴R⁵N—C(O)—; Wis H, Cl, NHR⁹ or OR⁸; R¹ is chosen from alkyl andC₁-C₃-alkylcycloalkyl; R², R³ and R⁵ are H; R⁴ is C₁-C₄-alkylaryl orC₁-C₄-alkylheteroaryl; R⁸ is C₁-C₄-alkylaryl; R⁹ is chosen fromhydrogen, alkyl, fluoroalkyl, (C₁-C₄-alkoxy)alkyl,(C₁-C₄-alkylthio)alkyl, C₁-C₄-alkylcycloalkyl, C₁-C₄-alkylaryl,heterocyclyl, C₁-C₄-alkylheteroaryl, C₁-C₄-alkylheterocyclyl; and m andn are zero.
 12. A 2-pyrimidinamine according to claim 11 wherein W isNHR⁹ and R⁹ is

wherein R¹⁴ is chosen from H, F, Cl, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁵ is chosen from H, OCH₃ and Cl.
 13. Acompound of formula

wherein: A is R⁴R⁵N—(O)—; Q is is chosen from imidazolyl and pyrrolyl; Wis NHR⁹; R¹ is chosen from cyclohexylmethyl; 2-methylpropyl and3-methyl-1-butyl; R², R³ and R⁵ are H; R⁴ and R⁹ are benzyl orsubstituted benzyl; m is zero; and n is zero.
 14. A compound of formula

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is

having the R configuration at the carbon indicated with an asterisk,wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl; orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 15. A pyrimidine according to claim 9 wherein R⁴ is

having the R configuration at the carbon indicated with an asterisk. 16.A compound of formula

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—C(O)—;

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom aryl, —CH₂R¹³, —CH═N—OCH₃ and

heteroaryl other than 1-imidazolyl and 1-triazolyl; W is chosen from H,Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and —NHC(O)R¹¹, with theproviso that when Q is imidazolyl, W is not H, Cl, F or R⁸; R¹ is chosenfrom alkyl, cycloalkyl, alkenyl, C₁-C₃-alkylcycloalkyl, heterocyclyl,C₁-C₃-alkylheterocyclyl, aryl, C₁-C₃-alkylaryl, heteroaryl,C₁-C₃-alkylheteroaryl, (C₁-C₃-alkyloxy)alkyl,(C₁-C₃-alkyloxy)cycloalkyl, (C₁-C₃-alkylthio)alkyl,(C₁-C₃-alkylthio)cycloalkyl and (C₁-C₃-alkylsulfonyl)alkyl; R² is H orC₁-C₃-alkyl, or R¹ and R² taken together form a 5- to 7-membered ringstructure optionally containing O, S or NR¹²; R³ is H or C₁-C₆-alkyl,or, when n is zero, R² and R³ taken together may form a 6-membered ring,which may be fused to a six-membered saturated or aromatic carbocycle;R⁴ is chosen from H, aryl, heteroaryl, C₁-C₄-alkyl substituted with fromone to three aryl or heteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl, orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 17. A 4-pyrimidinamine according to claim 16, wherein Z isCH, having the formula


18. A 4-pyrimidinamine according to claim 17 wherein Q is chosen frommethylimidazolyl, pyrrolyl, methylpyrrolyl, pyrazolyl, methylpyrazolyl,furanyl, methylfuranyl, thienyl, oxazolyl, thiazolyl, pyridinyl,quinolinyl, 1-methylpyrimidin-2-onyl, phenyl, fluorophenyl,hydroxymethyl, 2-imidazolyl, tetrahydropyranyloxymethyl,imidazolylmethyl, pyrrolylmethyl, —CH═N—OCH₃ and


19. A 4-pyrimidinamine according to claim 18 wherein: Q is chosen frompyrrol-1-yl, imidazol-1-yl, furan-3-yl, 2-methylimidazol-1-yl and4-methylimidazol-1-yl; A is R⁴R⁵N—C(O)—; W is Cl, NRH⁹, N(CH₃)R⁹, OR⁸,SR⁸, R⁸, morpholin-4-yl,

R¹ is chosen from alkyl, cycloalkyl, C₁-C₃-alkylaryl,C₁-C₃-alkylcycloalkyl, C—C₃-alkylheterocyclyl, C₁-C₃-alkylheteroaryl;R², R³ and R⁵ are H; R⁸ is C₁-C₄-alkylaryl; R⁹ is chosen from hydrogen,alkyl, substituted alkyl, (C₁-C₄)-alkoxy, C₁-C₄-alkylcycloalkyl,C₁-C₄-alkylaryl, heterocyclyl, C₁-C₄-alkylheteroaryl,C₁-C₄-alkylheterocyclyl; and m and n are zero.
 20. A 4-pyrimidinamineaccording to claim 19 wherein W is NHR⁹ and R⁹ is chosen from hydrogen;methyl; ethyl; 2,2,2-trifluoroethyl; allyl; cyclopropyl; 2-cyanoethyl;propargyl; methoxy; methoxyethyl; cyclopropyl; cyclopropylmethyl;(methylthio)ethyl; 3-methoxypropyl; 3-pyridyl; 2-(3-pyridyl)ethyl;2-(2-pyridyl)ethyl; 3-pyridylmethyl; 4-pyridylmethyl;4-pyridylmethyl-N-oxide; 2-pyridazinylmethyl; sulfolan-3-yl;3-tetrahydrofuranyl; 2-tetrahydrofuranylmethyl; 3-(1-imidazolyl)propyl;1-t-butoxycarbonyl-4-piperidinyl;1-t-butoxycarbonyl-4-piperidinylmethyl; 2-(hydroxyimino)propyl;2-(methoxyimino)propyl; 2-oxo-1-propyl; and

wherein R¹⁴ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,OH, SO₂CH₃, N(CH₃)₂ and COOH; R¹⁵ is chosen from H, OCH₃ and Cl; and pis 1 or
 2. 21. A 4-pyrimidinamine according to claim 19 wherein W is

R¹² is t-butoxycarbonyl, methoxyacetyl or phenyl.
 22. A 4-pyrimidinamineaccording to claim 16 wherein Z is CH; A is

R¹ is chosen from n-butyl; cyclohexylmethyl; cyclopentylmethyl;2-methylpropyl; 3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl;benzyl; 2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl;4-chlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and1,1-dimethylethyl; R² and R³ are H; Q is pyrrolyl; W is NHR⁹; and R⁹ isalkyl, cycloalkyl or

wherein R¹⁴ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁵ is chosen from H, OCH₃ and Cl.
 23. Apyrimidine according to claim 16 wherein: A is R⁴R⁵N—C(O)—; R¹ is chosenfrom isopropyl; n-butyl; cyclohexylmethyl; cyclopentylmethyl;naphthylmethyl; cyclohexylethyl; 2-methylpropyl; 3-methyl-1-butyl;cyclohexyl; 2,2-dimethylpropyl; benzyl; 2-thienylmethyl;1-t-butoxycarbonyl-4-piperidinyl; 4-methoxybenzyl; 4-chlorobenzyl;3,4-dichlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and1,1-dimethylethyl; R², R³ and R⁵ are H; R⁴ is pyridinyl,pyridinylmethyl, indanylmethyl, furanylmethyl, tetrahydronaphthalenyl,substituted phenyl, or

R¹⁶ is chosen from H, Cl, F, CN, NO₂, SO₂NH₂, CF₃, CH₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁷ is chosen from H, OCH₃, F and Cl. 24.A pyrimidine according to claim 16 wherein R⁴ is


25. A pyrimidine according to claim 24, wherein one of J¹ and J² is Hand the other is H, Cl or CN and G is chosen from —CH₂—, —CH₂CH₂—,—OCH₂—, —O— and —CH₂N(lower alkyl)-.
 26. A 2-pyrimidinamine according toclaim 16, wherein Y is CH, having the formula


27. A 2-pyrimidinamine according to claim 26 wherein Q is chosen frompyrrolyl, pyridinyl, fluorophenyl and 2-thienyl.
 28. A 2-pyrimidinamineaccording to claim 27 wherein A is R⁴R⁵N—C(O)—; W is H, Cl, NHR⁹ or OR⁸;R¹ is chosen from alkyl and C₁-C₃-alkylcycloalkyl; R², R³ and R⁵ are H;R⁴ is C₁-C₄-alkylaryl or C₁-C₄-alkylheteroaryl; R⁸ is C₁-C₄-alkylaryl;R⁹ is chosen from hydrogen, alkyl, fluoroalkyl, (C₁-C₄-alkoxy)alkyl,(C₁-C₄-alkylthio)alkyl, C₁-C₄-alkylcycloalkyl, C₁-C₄-alkylaryl,heterocyclyl, C₁-C₄-alkylheteroaryl, C₁-C₄-alkylheterocyclyl; and m andn are zero.
 29. A 2-pyrimidinamine according to claim 28 wherein W isNHR⁹ and R⁹ is

wherein R¹⁴ is chosen from H, F, Cl, CN, NO₂, SO₂NH₂, CF₃, COOCH₃, OCH₃,SO₂CH₃, N(CH₃)₂ and COOH; and R¹⁵ is chosen from H, OCH₃ and Cl.
 30. A2-pyrimidineamine according to claim 26 wherein R⁴ is

one of J¹ and J² is H and the other is H, Cl or CN and G is chosen from—CH₂—, —CH₂CH₂—, —OCH₂—, —O— and —CH₂N(lower alkyl)-.
 31. A4-pyrimidinamine according to claim 16, wherein X is CH, having theformula


32. A 4-pyrimidinamine according to claim 31 wherein Q is pyrrolyl and mand n are zero.
 33. A 4-pyrimidinamine according to claim 32 wherein: Ais R⁴R⁵N—C(O)—; W is NHR⁹; R¹ is chosen from cyclohexylmethyl;2-methylpropyl and 3-methyl-1-butyl; R², R³ and R⁵ are H; and R⁴ and R⁹are benzyl or substituted benzyl.
 34. A 4-pyrimidineamine according toclaim 31 wherein R⁴ is

one of J¹ and J² is H and the other is H, Cl or CN and G is chosen from—CH₂—, —CH₂CH₂—, —OCH₂—, —O— and —CH₂N(lower alkyl)-.
 35. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to any of claims 1, 6, 9, or
 14. 36. Apharmaceutical composition according to claim 35 additionally comprisinga steroidal or nonsteroidal antiinflammatory drug (NSAID).
 37. Apharmaceutical composition according to claim 35 additionally comprisinga cyclooxygenase inhibitor.
 38. A pharmaceutical composition accordingto claim 35 additionally comprising a selective cyclooxygenase-2inhibitor.
 39. A pharmaceutical composition according to claim 35additionally comprising a selective cyclooxygenase-1 inhibitor.
 40. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim
 16. 41. A pharmaceuticalcomposition according to claim 40 additionally comprising a steroidal ornonsteroidal antiinflammatory drug (NSAID).
 42. A pharmaceuticalcomposition according to claim 40 additionally comprising a nonsteroidalantiinflammatory drug (NSAID).
 43. A pharmaceutical compositionaccording to claim 42 wherein said NSAID is chosen from arylpropionicacids, arylacetic acids, arylbutyric acids, fenamic acids,arylcarboxylic acids, pyrazoles, pyrazolones, salicylic acids; andoxicams.
 44. A pharmaceutical composition according to claim 40additionally comprising a cyclooxygenase inhibitor.
 45. A pharmaceuticalcomposition according to claim 44 wherein said cyclooxygenase inhibitoris ibuprofen or a salicylic acid derivative.
 46. A pharmaceuticalcomposition according to claim 40 additionally comprising a selectivecyclooxygenase-2 inhibitor.
 47. A pharmaceutical composition accordingto claim 46 wherein said selective cyclooxygenase-2 inhibitor isrofecoxib or celecoxib.
 48. A pharmaceutical composition according toclaim 40 additionally comprising a selective cyclooxygenase-I inhibitor.49. A pharmaceutical composition according to claim 40 additionallycomprising a steroidal antiinflammatory drug.
 50. A pharmaceuticalcomposition according to claim 49 wherein said steroidalantiinflammatory drug is chosen from finasteride, beclomethasone andhydrocortisone.
 51. A method of treating vasculopathy comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of formula I

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl, orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 52. The method according to claim 51 wherein saidvasculopathy is diabetic vasculopathy.
 53. The method according to claim51 wherein said vasculopathy is hypertensive vasculopathy.
 54. A methodof treating asthma comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of formula I

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl, orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 55. A method of treating pain or hyperalgesia comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of formula I

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl; orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 56. The method according to claim 55 wherein said pain ischronic pain, pain associated with inflammation or dental pain.
 57. Themethod of treating pain or hyperalgesia according to claim 55additionally comprising administering a steroidal or nonsteroidalantiinflammatory drug (NSAID).
 58. The method of treating pain orhyperalgesia according to claim 57 wherein an NSAID is administered. 59.The method of treating pain or hyperalgesia according to claim 55additionally comprising administering a cyclooxygenase inhibitor. 60.The method of treating pain or hyperalgesia according to claim 59wherein said cyclooxygenase inhibitor is a selective cyclooxygenase-2inhibitor.
 61. The method of treating pain or hyperalgesia according toclaim 59 wherein said cyclooxygenase inhibitor is a selectivecyclooxygenase-1 inhibitor.
 62. A method of treating post-capillaryresistance or diabetic symptoms associated with insulitis comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of formula I

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃ and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl; orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.
 63. The method according to claim 62 wherein said diabeticsymptoms associated with insulitis comprise hyperglycemia, diuresis,proteinuria and increased nitrile and kallikrein urinary excretion. 64.A method of treating edema comprising administering to a subject in needof such treatment a therapeutically effective amount of a compound offormula I

wherein: two of X, Y and Z are N and the other of X, Y and Z is CH; A isA¹ or A²; A¹ is R⁴R⁵N—C(O)—,

A² is chosen from R⁷C(O)NH—, R⁷S(O)₂NH—, R⁴NH—, and R⁴O—; Q is chosenfrom heteroaryl, aryl, —CH₂R¹³, —CH═N—OCH₃ and

W is chosen from H, Cl, F, R⁸, C₁-C₄-alkylaryl, —OR⁸, —SR⁸, —NR⁹R¹⁰ and—NHC(O)R¹¹, with the proviso that when Q is imidazolyl, W is not H, Cl,F or R⁸; R¹ is chosen from alkyl, cycloalkyl, alkenyl,C₁-C₃-alkylcycloalkyl, heterocyclyl, C₁-C₃-alkylheterocyclyl, aryl,C₁-C₃-alkylaryl, heteroaryl, C₁-C₃-alkylheteroaryl,(C₁-C₃-alkyloxy)alkyl, (C₁-C₃-alkyloxy)cycloalkyl,(C₁-C₃-alkylthio)alkyl, (C₁-C₃-alkylthio)cycloalkyl and(C₁-C₃-alkylsulfonyl)alkyl; R² is H or C₁-C₃-alkyl, or R¹ and R² takentogether form a 5- to 7-membered ring structure optionally containing O,S or NR¹²; R³ is H or C₁-C₆-alkyl, or, when n is zero, R² and R³ takentogether may form a 6-membered ring, which may be fused to asix-membered saturated or aromatic carbocycle; R⁴ is chosen from H,aryl, heteroaryl, C₁-C₄-alkyl substituted with from one to three aryl orheteroaryl residues,

wherein J¹ and J² are independently chosen from H, F, Cl, CN, NO₂ andCH₃, and G is chosen from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂O—,—CH₂CH₂O—, —OCH₂CH₂—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH₂—,—CH₂N(lower alkyl)-, —S—, —SO—, —SO₂—, —CH₂S—, —SCH₂—, —CH₂SO—, —SOCH₂—,—CH₂SO₂—, and —SO₂CH₂—; R⁵ is H or C₁-C₃-alkyl, with the proviso thatboth R³ and R⁵ cannot be alkyl; R⁶ is aryl; R⁷ is aryl orC₁-C₃-alkylaryl; R⁸ is chosen from alkyl, aryl, heteroaryl, substitutedalkyl, C₁-C₄-alkylaryl, C₁-C₄-alkylheterocyclyl andC₁-C₄-alkylheteroaryl; R⁹ is chosen from H, alkyl, alkenyl, substitutedalkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl,C₁-C₄-alkylcycloalkyl, (C₁-C₄-alkoxy)alkyl, (C₁-C₄-alkoxycarbonyl)alkyl,(C₁-C₄-alkylthio)alkyl, heterocyclyl, C₁-C₄-alkylheterocyclyl,C₁-C₄-alkylaryl, and C₁-C₄-alkylheteroaryl; R¹⁰ is H or C₁-C₃-alkyl; orR⁹ and R¹⁰ taken together may form a 5- to 7-membered ring structureoptionally containing O, S, SO, SO₂ or NR¹², said ring optionallysubstituted with —OH, —CN, —COOH or —COOCH₃; R¹¹ is aryl; R¹² is chosenfrom H, C₁-C₃-alkyl, alkoxycarbonyl, methoxyacetyl and aryl; R¹³ ischosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl; m is zero or one;and n is zero or one, with the proviso that when A is A², m and n cannotboth be zero.